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Objective Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. Methods All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. Results A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with β-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. Conclusions Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.

Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Relative contributions of local and systemic mechanisms of upper gastrointestinal (GI) injury following aspirin are unknown. Studies suggest that aspirin's GI risk is age related and that gastroprotection may be needed at therapy initiation. We determined acute gastroduodenal erosion and ulceration following low-dose aspirin and aspirin-phosphatidylcholine complex (PL2200) in subjects at risk of aspirin ulcers.In a randomized, single blind, multicenter active-controlled study, we compared upper GI damage of aspirin and PL2200 in healthy subjects (n=204, ages 50-74 years) following 7 days of oral 325 mg once daily, immediate release aspirin or PL2200.Overall, 42.2% of aspirin-treated subjects developed multiple erosions and/or ulcers, whereas 22.2% treated with PL2200 developed such damage (P=0.0027). Gastroduodenal ulcers were observed in 17.6% of aspirin-treated compared with 5.1% of subjects treated with PL2200 (P=0.0069).Low-dose aspirin induced a surprisingly high incidence of acute gastroduodenal ulcers in at risk subjects, highlighting that aspirin's upper GI risk begins early and may require gastroprotection. Local mechanisms of GI protection are important as aspirin's preassociation with surface-active phospholipids significantly reduced mucosal damage. PL2200 may be an attractive alternative or complement to proton pump inhibitors in older patients who are at risk of aspirin-induced ulceration. Longer-term studies assessing clinical GI events are desirable to confirm the clinical GI safety profile of PL2200.

The American College of Gastroenterology (ACG) Institute for Clinical Research and Education conducted a survey study to assess demographics, management strategies, and outcome for patients with gastrointestinal bleeding. This pilot project was intended to determine the feasibility of surveying the ACG membership about common clinical issues.Color-coded survey forms were sent to all ACG members and Fellows, with instructions to supply information about demographics, presenting symptoms, management, and outcome for bleeding patients and procedure-matched controls. Forms returned between June 1 and August 31, 1995, were tabulated and analyzed for differences between the bleeding group and procedure-matched controls.A total of 1235 forms were returned by respondents, 60% of whom were in private practice. Patient demographics indicated that bleeding patients were significantly older, more likely to be male, and more likely to use alcohol, tobacco, and prescription or over-the-counter aspirin or nonsteroidal anti-inflammatory drugs and anticoagulants than were controls. Upper GI bleeding accounted for 76% of bleeding events, with duodenal and gastric ulcers being the source in more than 50% of the upper GI bleeders. Diverticula was the most common bleeding source identified in lower GI bleeders. In the bleeding group, 78.8% were anemic, with 60.9% having hemoglobin of10 g/dl; 31% presented with orthostatic changes in blood pressure or shock. Most bleeding subjects, regardless of source, were hospitalized, 58.2% received blood transfusions, and 45.5% received endoscopic therapy. Rebleeding (11.2%), need for surgery (7.1%), and fatalities (2.1%) were uncommon. Over-the-counter aspirin and nonsteroidal anti-inflammatory drugs were used significantly more often in the bleeding population (47.6%) than in controls (19.4%).The success of the GI Bleeding Registry supports the feasibility of surveying ACG members about common clinical problems. Data suggest that ACG members manage sick patients with severe gastrointestinal bleeding who require hospitalization, transfusions, and endoscopic treatment. These preliminary results will serve as an impetus to conduct further survey studies of gastrointestinal bleeding and other common digestive disease conditions.

Comparison of the onset of the acid-reducing effect of famotidine/antacid combination tablets, omeprazole 20 mg, and placebo on gastric pH profiles in healthy volunteers

The linkage between gastroduodenal mucosal injury and nonsteroidal anti-inflammatory drugs (NSAIDs) is now well established. Fifteen percent to 20% of patients taking these agents develop gastric or duodenal ulcer, and about 3% of this group goes on to experience hemorrhage or perforation. Gastrointestinal (GI) complications occur primarily in certain high risk groups, notably elderly female patients and patients with a prior history of peptic ulcer or GI bleeding. Recently, two new NSAIDs, nabumetone and etodolac, which are reportedly safer because they selectively inhibit prostaglandin synthesis in target tissues but spare that in the stomach, have been introduced in the United States. Further, data from clinical trials of oxaprozin, an NSAID not yet available in the United States, indicate that this agent may have a better safety profile than older NSAIDs. A review of the literature concerning the mucosal toxicity of these three agents reveals that the overall ulceration and major complication rate is low. However, a direct comparison with older NSAIDS in a large group of patients in a dose with similar efficacy is lacking.

Numerous studies have shown that higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased levels of mucosal injury and ulceration in both normal volunteers and patients. The present dose-ranging study was designed to determine whether escalating doses of a commonly prescribed NSAID, flurbiprofen, when expressed as mg/kg dosages, were associated with increased mucosal injury and ulceration. Subjects received either the recommended dose of 300 mg/day of flurbiprofen (N = 10), or the higher than recommended doses of 400 mg/day (N = 20) and 500 mg/day (N = 10), for a period of 7 days. Endoscopic examination was performed on day 0 and day 7, and the stomach was evaluated on day 7 for mucosal injury on a 0-4 scale, and for the presence or absence of ulcer. One gastric ulcer was seen in each of the 300- and 400-mg groups. However, in the 500 mg/day group, four gastric ulcers were seen (40%) (p = 0.04). Three of the six subjects developing gastric ulcer were of a fairly low body weight (two women, one man), and when the data were analyzed on a mg/kg basis, all six ulcers occurred in 19 of the 40 subjects receiving5.95 mg/kg, whereas no gastric ulcers were seen in the 21 subjects receiving dosages below that level (p0.01). These data suggest that, at least for this agent, a threshold level may exist above which gastric ulcers are much more likely to occur. This may in part explain why elderly debilitated, low-body-weight female patients are more prone to NSAID-related gastric ulcer.

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.

This study asked whether Helicobactor pylori infection accentuated the severity of NSAID-induced mucosal injury of the stomach or duodenum. We evaluated the severity of acute mucosal injury and H. pylori status in 61 normal volunteers (ages 22-43 yr) receiving naproxen (1000 mg, n = 30) or aspirin (3900 mg, n = 31) daily for 7 days. NSAID-induced gastric and duodenal mucosa each were endoscopically graded separately for hemorrhages and erosions-ulcers on a scale of 0 to 4. H. pylori infection was identified by a sensitive and specific ELISA. Nine of the 30 subjects in the naproxen group and 12 of the 31 subjects in the aspirin group were H. pylori positive (p = NS). There was no statistically significant difference between the frequency of mucosal hemorrhage in those with and those without H. pylori infection (44% compared with 33% for those receiving naproxen and 90% of those receiving ASA, p = NS for each). There were also no differences in the frequency or severity of erosive mucosal injury seen, e.g., acute ulcers were found in 16.5% and 17.5% of infected and uninfected subjects, respectively. We conclude that the presence of H. pylori infection does not influence the degree or type of mucosal damage associated with the acute administration of naproxen or aspirin.

The effect on the gastroduodenal mucosa of alcohol combined either with aspirin or ibuprofen was studied in 60 normal volunteers. The volunteers were divided into six groups comprised of 10 subjects receiving ibuprofen, placebo, or aspirin with or without alcohol. Medications consisted of 1) three 325-mg aspirin tablets, or three identical placebo tablets, 2) one 600-mg ibuprofen tablet, and 3), three ounces of 100 proof vodka diluted in 6 ounces of orange juice, or alcohol placebo made by diluting 3 ounces of water in orange juice. All subjects received 4 doses over a 24-hr period and underwent endoscopic examination the following morning. The gastroduodenal mucosa was graded according to a 0 to 4 + scale. Aspirin caused considerably greater duodenal and gastric damage than did either ibuprofen or placebo. The addition of alcohol to all drugs increased the damage seen in the stomach but not to a significant degree; this effect was slightly more pronounced with ibuprofen than with placebo or aspirin and approached significance (0.1 greater than p greater than 0.05). These results are compatible with alcohol being a mild damaging agent or a potentiating agent for damage from other drugs.

Seventy-three upper gastrointestinal endoscopic polypectomies were performed in 63 patients over a period of five years. Thiry-eight patients (52%) had adenomatous polyps, two of which contained carcinoma in situ and 26 (36%) were inflammatory in nature. Four lesions were removed from the duodenum. Hemodynamically significant hemorrhage occurred in five cases and persistent symptomatic ulcer in three cases. All complications occurred early in the series and responded to conservative measures. There was no mortality or need for surgical intervention in any case. It was concluded that: 1. upper gastrointestinal tract endoscopic polypectomy is a safe and relatively simple procedure; 2. postprocedural complications can be markedly reduced by prophylactic conservative antiulcer therapy and 3. especially in the area of adenomatous polyps, excision of the entire lesion is superior to biopsy in the detection of early malignancy.

Unlike the clinical trials of the previous decade, those conducted during the past 10 yr have had considerable impact on current therapeutic practices in the management of disorders of the upper gastrointestinal tract. This article reviews the clinical experience from 1975 to 1985 that pertains to the effectiveness of antacids compared to placebo and other anti-ulcer medications in the prevention and treatment of duodenal and gastric ulcers, stress ulceration and acute gastrointestinal bleeding, and gastroesophageal reflux disease.

Patients who have demonstrated a gastric mucosal sensitivity to aspirin often react to other nonsteroidal, anti-inflammatory drugs to a similar or lesser degree. In a single-blind crossover study, five healthy volunteers who had previously developed erosive gastritis secondary to one week of aspirin therapy were randomly assigned to seven-day courses of treatment with ibuprofen, tolmetin and placebo. Treatment schedules were separated by washout periods to eliminate residual drug effects. Ibuprofen produced less gastric mucosal injury than tolmetin and, over all, appeared to be better tolerated. It was also noted that clinical symptoms often do not reflect the severity of gastroscopic findings, which may explain silent hemorrhaging in patients treated with agents of this type.

Sucralfate is a nonsystemic drug used in the therapy of peptic ulcer disease. It is an aluminum salt of a sulfated disaccharide which adheres to ulcerated sites and forms a cytoprotective barrier to acid peptic digestion. The purposes of this study were to determine whether sucralfate had antacid activity in humans and to test the validity of the in vitro antacid qualifying test by comparing its results for tableted products with those of in vivo studies. In the in vitro antacid qualifying test Maalox #1 (4 tablets) passes and sucralfate (1 gm.) failed. These findings were consistent with the results of in vivo tests utilizing a telemetric device, the Heidelberg capsule and tube aspirations. We conclude that sucralfate does not possess antacid properties and that the results of the standard in vitro antacid qualifying test correlated well with those of in vitro studies.

Ibuprofen, a commonly proscribed nonsteroidal anti-inflammatory drug that is also available in many countries, including the United States, without a prescription, is known to cause hemorrhage and erosion of the gastroduodenal mucosa. This study was conducted to compare the efficacy of 200, 100, and 50 micrograms of misoprostol and placebo administered qid for 6 days, with a final dose on the morning of the 7th day, in the prevention of gastric and duodenal lesions induced by the concurrent administration of 800 mg of ibuprofen qid. A total of 120 healthy subjects with endoscopically normal gastric and duodenal mucosae were enrolled in the study. The endoscopic examination was repeated 2 h after the final dose on day 7, and the mucosae were graded on a 0 to 4+ scale. In the stomach, all three misoprostol groups were significantly more protective than placebo and did not differ significantly from each other. In the duodenum, the endoscopic scores of the 200- and 100-micrograms misoprostol groups, but not the 50-micrograms group differed significantly from placebo. The 200- and 100-microgram groups did not differ significantly from each other, but both differed from the 50-micrograms group for duodenal mucosal injury. Subjective symptoms thought to be primarily attributable to the NSAID (e.g., pain, indigestion/heartburn and nausea) were recorded by each subject in a diary. Subjects in the 200-micrograms misoprostol group attained the greatest degree of mucosal protection and had a significantly higher incidence of indigestion/heartburn and abdominal pain than the placebo group. One can conclude that misoprostol in both antisecretory (200- and 100-micrograms) and non-antisecretory (50-micrograms) doses protects the gastric mucosa from injury from high anti-inflammatory doses of ibuprofen (3200 mg/day). Only the antisecretory doses (100 and 200 micrograms qid) were effective in the duodenum, suggesting that acid suppression is necessary for mucosal protection to occur in the duodenum.

Twenty-five normal volunteers were randomized into five equal parallel groups. Groups I received ibuprofen (2,400 mg./day); group II received tolmetin (2,000 mg./day); group III received indomethacin (150 mg./day); group IV received naproxen (750 mg./day) and group V received placebo (four tablets daily). All drugs were given on a q.i.d. basis except naproxen which was given b.i.d. The doses selected represented the manufacturer's highest recommended dosage for the treatment of arthritic disorders. A single-blind technic was used in which the investigators were unaware of which drug each volunteer was taking. Upper gastrointestinal endoscopy and photography were carried out before and after seven days of administration of each medication. Gastric and duodenal mucosal injury was graded on a 0-4 + scale. Three of the four drugs studied produced essentially equal gastric and duodenal mucosal injury with tolmetin producing the most damage followed by naproxen and indomethacin. Ibuprofen produced gastric mucosal injury equivalent to that seen with naproxen and indomethacin but no duodenal mucosal injury was seen with this drug. Extremely poor correlation was found between subjective symptomatology and endoscopic findings.