whether prenylated proteins also are present in the more complex plant RNA viroids or other related viruses. In addition to providing a greater understanding of the life cycle of HDV and clarifying the biologic importance of the two isoforms of HDV antigen, it points the way toward the possible development of antiviral therapy. There is clearly a need for new treatment strategies because
current antiviral therapy of HDV infection is less than satisfactory (Hepatology 1991;13:1052-1056). In addition to the treatment of patients with chronic HDV infection, the effect ofprenylation inhibition on HDV infection might be studied in the liver transplantation setting because HDV reinfection may occur in as many as 80% of HBsAg-positive patients with HDV infection and cirrhosis who survive transplantation (Gastroenterology 1991;101:16491655). Of course, a key question that must be asked before human studies can be undertaken is whether inhibition of prenylation affects HDV infection in animals with hepadnavirus and HDV infections. Will prenylation inhibition reduce the level of viremia? Will it affect the hepatic replication of the HDV genome? What are the in vivo consequences of impaired packaging of HDV? Will the accumulation of nonparticle HDV intermediates that cannot be assembled into HDV particles have a deleterious influence on the hepatocyte? Finally, the degree and safety of prenylation inhibition must be demonstrated in infected animals. Whether such agents as lovastatin, compactin, or other inhibitors of hepatic 3hydroxy-3-methylglutaryl coenzyme A reductase can prevent the synthesis of the prenyl intermediates required for prenylation of the large HDV antigen in infected species has not yet been shown. Other nonenzymatic approaches to prenylation inhibition, as briefly outlined by the authors, are also exciting concepts. I hope these investigators will continue to pursue this research. The payoff may be great. R. S. KOFF,
BLEEDING ESOPHAGEAL INJECT OR BAND?
GV, GoffJS, Michaletz-Onody PA, et al. (University of Colorado, Denver, Colorado; Baylor College of Medicine, Houston, Texas; University of Southern California, Los Angeles, California; and Oregon Health Sciences Center, Portland, Oregon). Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J of Med 1992;326:1527-1532 (June).
Endoscopic sclerotherapy (ES) is an accepted therapy for both acute and obliterative treatment of bleeding esophageal varices, although complication rates of 15%-40% are reported. Endoscopic variceal ligation (EVL), or banding, has recently been reported effective for bleeding esophageal varices and is said to have a lower complication rate than sclerotherapy. The present study is the first prospective comparison between endoscopic injection sclerotherapy and endoscopic band ligation. One hundred thirty patients with either a documented actively bleeding esophageal varix or a recently bleeding esophageal varix were randomized to groups to receive either ES or EVL. Two hundred thirty consecutive patients accrued from four centers over 27 months were screened for entry into the study. Exclusion criteria included prior endoscopic or surgical therapy for varices, gastric fundic varices, intercurrent illness with death expected within 12 months, or symptoms of esophageal dysfunction. Previous treatment with balloon tamponade, vasopressin, or J3-
adrenergic antagonists did not disqualify patients, although B-blockers were not permitted during the trial. The investigators each had prior experience with ES and each had performed at least 10 prior EVL. ES therapy consisted of a maximum of 20 mL per session with no more than 2 mL of 1.0% tetradecyl sulfate injected at each site intravariceally. EVL therapy consisted of the placement of l-8 bands per session. Repeat therapy occurred at intervals of 5-21 days or more often for recurrence of bleeding, until all varices were reduced to grade 1 (~3 mm) or eradicated. After eradication of varices the patients underwent endoscopic surveillance every 3 months. Sixty-six patients were randomized to receive ES and 64 patients to receive EVL. One patient was dropped from the ES group due to inappropriate randomization, leaving 65 patients for the trial. The severity of liver disease, etiology of liver disease (80% alcoholic), size of varices, transfusion requirement, and the male-to-female ratio (4.5:1) were similar in the two groups. Study follow-up was approximately 320 days for the 88 patients who remained in the study for longer than 30 days. One fifth of patients in each treatment group were actively bleeding at the time of index treatment, with equal hemorrhage control obtained with either treatment (10 of 13 patients in the ES group and 12 of 14 in the EVL group). Thirty-one patients (48%) in the ES group had 44 episodes of recurrent bleeding, and 23 (36%) in the EVL group had 33 episodes of recurrent hemorrhage (P = 0.072). The site of recurrent bleeding was most often an esophageal varix in both groups. Treatment-induced recurrences of bleeding, resulting from ulceration or mucosal sloughing, occurred in 4 patients in the ES group and in 5 patients in the EVL group. Eradication of varices for patients who remained in the study for more than 30 days occurred in 22 of 39 (56%) in the ES group and in 27 of 49 (55%) in the EVL group. The number of treatments required to eradicate all varices was one less in the EVL group (four vs. five sessions). More than 50% of all deaths occurred within 30 days of entry into the study. The overall survival rate in the EVLtreated patients, 46 of 64 (72%), was better than the survival rate in the ES group, 36 of 65 (55%) (P = 0.041). Survival for Child’s class C patients was the same with either treatment. Eighty percent of patients in both treatment arms were Child’s class A or B, with EVL producing a better survival rate in these patients (P = 0.046). Complications were defined as any untoward event (pneumonia, pleural effusion, bacterial peritonitis, and esophageal stricture or perforation) that required active treatment or prolonged hospitalization. Complications occurred in 14 of 65 (22%) in the ES group and in 1 of 64 (2%) in the EVL group (P < 0.001). The most common complication in the ES group was esophageal stricture, which occurred in 8 patients (12%). Pneumonia, bacterial peritonitis, and other pulmonary complications accounted for the rest of the complications; 7 (11%) in the ES group and 1 (2%) in the EVL group. Four of 29 (14%) deaths in the ES group and 1 of 18 (6%) deaths in the EVL group were felt to result from complications (difference not significant). The authors conclude that endoscopic band ligation of esophageal varices is superior to ES for the treatment of
bleeding esophageal varices in terms of both complications, except for bleeding from procedural-induced erosions, and survival. They attribute the better survival to fewer recurrences of bleeding and fewer infectious complications. Comment. Endoscopic band ligation of esophageal varices was first described by the authors in 1986 (Gastrointest Endosc 1986;32:230-233). Experimental models in dogs were used to perfect the technique and determine the pathophysiological changes that occur with EVL. EVL appears to cause strangulation and necrosis of banded tissue with tissue sloughing occurring 3-7 days after banding. During the first posttreatment week shallow ulcers commonly occur with subsequent submucosal scar formation after approximately 14 days. This scar occurs without disruption of the muscularis propria (Gastrointest Endosc 1988;34:113-117). The authors conclude that EVL is superior to ES. This conclusion should be based on several comparisons between ES and EVL including assessment of (a) efficacy for both cessation of bleeding and prevention of rebleeding, (b) complications, (c) ease of use and cost of the treatment, and (d) overall effect on patient survival. The present trial confirms prior studies showing the efficacy of EVL for control of active variceal hemorrhage. Successful control of acute hemorrhage by either ES or EVL occurs in >90% of patients (Am J of Surg 1990;160:32-36; Am J of Surg 1990;159:21-26). Recurrent bleeding rates in prior ES trials are highly variable but range from 22% to 58% (Am J Gastroenterol 1987:82:823-830). In the present study recurrent bleeding rates in both the ES group (48%) and the EVL group (36%) are similar, although the high number of undetermined sources of recurrent bleeding (21 of 77 or 27%) in the current trial is bothersome. At variance with prior sclerotherapy trials is the low success rate for variceal eradication in patients who remained in the trial for at least 1 month. Successful eradication occurred in 56% of the ES-treated patients and in 55% of the EVL group. This rate is considerably lower than the 80%-87% eradication rates achieved with ES in other trials (Gastrointest Endosc 1990;36:567-571; Hepatology 1985;5:827-830). The reason for the low eradication rate in the present study is not clear. A maximum of 20 mL of 1.0% sodium tetradecyl sulfate was used, although the authors do not give the average amount injected per session. It is possible that the eradication rate would be higher and the rebleeding rate lower in the ES group if more aggressive sclerotherapy had been performed. Complications of ES are common, although infrequently fatal. The mortality rate for ES has been shown to range from 2% to 12%, and the overall significant complication rate ranges from 20% to 40% (Am J of Gastroenterol 1987;82:823-830). Many complications of ES are actually side effects (postprocedural chest pain, fever, and fleeting infiltrates) that do not result in additional morbidity or mortality and thus were not defined as complications in the present study. Esophageal strictures without any apparent long-term sequelae accounted for over half of the complications in the ES group. A recent preliminary report showed that ES caused esophageal dysmotility and peritreatment reflux in three patients, which did not occur in the two EVL-treated patients [Gastroenterology 1992;102:A2 (abstr)]. A comparative study examining the esophageal ulceration rate following ES and EVL showed that EVL actually produces a larger surface area of ulceration than ES but that the ulcers have less depth and heal faster (Gastrointest Endosc 1992;38:285). The lesser depth of injury presumably accounts for the lower stricture rate of EVL. In the present study bacterial peritonitis (three patients) and pneumonia (four patients) resulted in four deaths in the ES group compared with only one episode of pneumonia in the EVL group which also resulted in death. Bacteremia infrequently accompanies elective ES but follows emergency sclerotherapy in 13% of
GASTROENTEROLOGY Vol. 103, No. 6
cases (Gastroenterology 1991;101:1642-1648). It has recently been shown that bacteremia does not follow EVL (Gastrointest Endosc 1992;38:336-337), although this is an unlikely explanation for the difference in infection rate in the present study because bacteremia-induced clinical infections are so rare. The authors speculate that either the overtube protects against aspiration pneumonia and/or that injection of a sclerosant may impair host immune mechanisms. Eighty-one percent of patients entered into the current trial were Child-Pugh class A or B with only 19% class C. This is at odds with previous sclerotherapy trials in which a much larger percentage were class C cirrhotics (Gastroenterology 1989;96:899906). The authors report superior overall survival with EVL vs. ES (P = 0.041) and attribute this to less rebleeding and fewer infections. Of note the survival advantage was not seen in the Child’s class C patients, who are the patients most commonly encountered in practice. It has been suggested that Child’s class is not a significant predictor of mortality in esophageal hemorrhage and that more accurate predictors of survival are encephalopathy, prothrombin time, and 72-hour red cell transfusion requirements [Gastroenterology 1992;102:Alll (abstr)]. The Child’s class, prothrombin time, and transfusion requirements were statistically similar, although in the ES group the trend was higher, and data for encephalopathy were not given. The difference in survival for the Child’s class A and B patients, without a significant difference in deaths due to major complications, suggests that the two treatment groups may have differed at entry. EVL is not technically difficult for experienced endoscopists. This study did not comment on the difficulty of banding small varices, although it has been reported that eradication of small varices is difficult with apparent rebleeding occurring in the small varices (Endoscopy 1992;24:52-57). Procedural costs for ES and EVL are comparable (Gastrointest Endosc 1991;37:670-672), although if one takes into consideration that EVL requires fewer sessions, EVL may be less costly for the treatment of varices (Gastrointest Endosc 1992;38:285). Is EVL superior to ES in treating esophageal varices? The present study was unblinded (as necessitated by its design), which raises the question of unintentional bias. The claim for improved survival with EVL requires further confirmation because the differences reported could be explained by differing status at entry. The low rate of variceal eradication in this study using either technique questions the adequacy of the ES treatments. Despite these concerns, EVL is now shown to be as effective as ES for both the cessation of variceal hemorrhage and for the prevention of rebleeding. More significantly, the complication rate is lower with EVL. In addition to the complications examined in this study, the marked decrease in postprocedural chest pain and fever are certainly important for patient comfort and compliance with therapy. Additionally, this technique is simple and cost effective. These factors alone make EVL a promising new treatment for bleeding esophageal varices. M. L.
KOCHMAN, M.D. G. H. ELTA, M.D.
Comment. ES is considered the treatment of choice for bleeding esophageal varices at present. Sclerotherapy is superior to medical management with vasopressin or balloon tamponade in halting active variceal bleeding, with success in 62%-100% of patients (JAMA 1986;255:497-500; Hepatology 1989;9:274-277; Hepatology 1985;5:580-583; Surg Gyn Obstet 1988;167:331-334). Six prospective, randomized trials comparing sclerotherapy and standard medical management provide information about short-term results (l-6 weeks) with sclerotherapy (JAMA 1986;255:497-500; Hepatology 1985;5:580-583; Surg Gyn Obstet 1988;167:331-334; N Engl J Med 1984;311:1594-1600; Acta Chir Stand 1985;151:449-