antacid combination tablets, omeprazole 20 mg, and placebo on gastric pH profiles in healthy volunteers

AJG – September, Suppl., 2003

pantoprazole on intragastric pH in healthy individuals and its role in the control of ‘Severe NVUGI bleeding.’ Methods: 16 healthy individuals were randomized to receive pantoprazole 80mg IV bolus followed by infusion at the rate of 8mg/h (Group A, n⫽8) or pantoprazole with ranitidine 100mg IV bolus followed by infusion at a rate of 12.5mg/h (Group B, n⫽8) and intragstric pH recording done for 24 h. In addition, 38 patients of severe active NVUGI bleed with shock (B.P.⬍100 mm systolic, fresh blood in NG aspirate) were randomized into two groups C and D (n⫽19, each group). Group C received same drugs as group A and group D as in B for 72 hours. Intragastric pH recording was done in 2 patients in each group C and D. Endoscopy and endotherapy (if required) was done in 2–20h. Results: 2 hour pH and mean pH value (area under curve) at 2h, 3h and 6 h were higher in group B than in group A (p⬍0.002). The causes of UGI bleeding were similar in both groups C and D. 15 patients in group C and 14 in group D stopped bleeding with pharmacotherapy within 2-14h and endotherapy was done in the rest. There was no difference in the average transfusion requirement (750⫾450ml in group C and 700⫾500ml in group D), rebleeding rate (2/19 in each group) and mortality due to uncontrolled bleed (1 patient in each group). Baseline intragastric pH was ⬎6 in all the four patients monitored from group C D and remained high during the next 24 h. Conclusions: In healthy individuals, addition of ranitidine to pantoprazole resulted in better acid control during the initial 6 hours. Good acid inhibition helped in control of NVUGI bleeding in majority of this selected group of patients presenting with severe active bleeding thus reducing the mortality. But adding ranitidine made no difference in intragastric pH or clinical outcome in patients presenting with severe active bleeding, possibly due to neutralization of gastric acid by the large amount of blood present in the stomach at the time of presentation

146 SYMPTOMS DO NOT PREDICT THE RESULT OF GASTRIC EMPTYING STUDIES Marten B. Duncan, D.O., Corrine Maydonovitch, B.S., Nizar Mukhtar, Roy K.H. Wong, M.D.*. Walter Reed Army Medical Center, Washington, DC. Purpose: The correlation between reported symptoms of patients and measurable physiologic abnormalities are inconsistent in patients presenting with dyspepsia, gastroesopahgeal reflux disease (GERD), and diabetes mellitus. We conducted a retrospective review of gastric emptying studies (GES) to determine if the clinical parameters used to obtain a study were predictive of an abnormal GES. Methods: A 3-year retrospective review of GES performed at Walter Reed Army Medical Center from January 1999 to December 2001 was performed. 156 of 165 GES studies were analyzed as nine studies had incomplete clinical data. GES were compared to reason for performing the studies: Diabetes mellitus, bloating, nausea and vomiting, abdominal pain and refractory GERD. Gastric emptying was performed following a scrambled egg sandwich (300 calories) containing 99m-technicium-sulfur colloid. Scintigraphic images were obtained at 15-minute intervals up to 90 minutes per clinic protocol. Data included demographic information and GES result were recorded and analyzed with a Chi-square test. Results: Of the156 patients reviewed, there were 62 men and 94 women, mean age of 48.6, range 19 to 88. The major reasons for performing the GES was diabetes mellitus (27), bloating (40), nausea and vomiting (34), abdominal pain (19), and refractory GERD (36). Delay of gastric emptying was similar in each group of patients, 29.6%, 22.5%, 26.5%, 21.1%, and 22.2% respectively, p⫽0.936. Increase in GES was noted in 22.2%, 17.5%, 20.6%, 15.8%, and 16.7% of patients respectively. GES were delayed in 26.2% of men and 23.5% of women with no statistical differences found within any subgroup. The percent of gastric retention had a similar distribution between groups, see figure.

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Conclusions: (1) Delayed gastric emptying was noted in 21 to 29% of all patients referred for GES. (2) Clinical symptoms do not predict the results of a GES. (3) The standard meal used in GES may not challenge gastric emptying enough to allow differentiation between various degrees of gastric emptying abnormalities.

147 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 Frank L. Lanza, M.D.*, Amy Replogle, B.S., Laura Stauffer, M.S., Christine Furtek, B.S., Jeffrey G. Levine, M.D. Houston Institute for Clinical Research, Houston, TX and Merck & Co., Inc., Blue Bell, PA. Purpose: Famotidine/antacid combination tablets (FACT) combine 10 mg of a potent H2 receptor antagonist with standard calcium and magnesium containing antacids. This combination has been shown to have the benefit of more rapid relief of symptoms than famotidine alone, and a longer duration of relief than antacid alone. Omeprazole (O) is a potent proton pump inhibitor (PPI), but the onset of symptom control is not usually reached after only one dose. The objective of this randomized, open-label, 3-period, crossover study was to compare the onset of the acid-reducing effect of FACT to that of O 20 mg (MUPS formulation) as measured by time to gastric pH ⱖ 3.0 and ⱖ 4.0. Duration was not explored. Methods: 24 healthy subjects underwent a prestudy visit and 3 treatment sessions, with each session separated by ⬃ 1 week. The 3 treatment sessions each included a single-dose of FACT, O 20 mg, or placebo (P). Subjects were randomly assigned to 1 of 6 treatment sequences and before each treatment session, subjects fasted overnight. During each treatment session, subjects’ intragastric pH was taken for a 3 hr period, starting 1 hr before treatment and extending 2 hrs post-treatment. Primary efficacy was the time to pH ⱖ 3.0, where pH ⱖ 3.0 was maintained for at least a 5 min interval. A value of pH ⱖ 3.0 was selected because a gastric pH level of 3.0 is considered a threshold for the efficacy of gastric antisecretory drugs. In addition, values of pH ⬎ 3.0 are observed infrequently during the fasting state and in the absence of medication. The secondary endpoint of time to pH ⱖ 4.0 was chosen because this is often a benchmark used for PPI therapy. Results: The median time to pH ⱖ 3.0 was 2.5 mins for FACT and ⬎ 2 hrs for O 20 mg and P (p ⬍ 0.001 for both comparisons v.s. FACT). All 24 FACT subjects reached a pH of ⱖ 3.0 during the 2 hr evaluation period. 23 of the 24 O 20 mg subjects failed to reach a pH ⱖ 3.0. All 24 P subjects failed to reach a pH ⱖ 3.0. For the secondary efficacy parameter, the

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AJG – Vol. 98, No. 9, Suppl., 2003

median time to pH ⱖ 4.0 was 3.5 mins for FACT and ⬎ 2 hrs for O 20 mg and P (p ⬍ 0.001 for both comparisons v.s. FACT). 22 FACT subjects reached a pH ⱖ 4.0 during the 2 hr evaluation period. All 24 O 20 mg and P subjects failed to reach a pH ⱖ 4.0. Conclusions: Subjects reached a pH of ⱖ 3.0 and pH ⱖ 4.0 significantly faster after consuming FACT compared with omeprazole 20 mg MUPS or placebo. 148 ESOMEPRAZOLE REDUCES GASTRIC AND DUODENAL ULCER DEVELOPMENT AMONG HIGH RISK NSAID USERS J. M. Scheiman*, N. Yeomans, C. J. Hawkey, N. J. Talley, L. Gothe, J. Sung, R. Jones, J. Naesdal. Univ. of Melbourne, Australia; Nottingham, United Kingdom; Mayo Clinic, Rochester; AstraZeneca R&D, Molndal, Sweden; Chinese Univ of Hong Kong, Hong Kong and London, United Kingdom. Purpose: The prevalence of gastric (GU) or duodenal ulcers (DU) in NSAID users is 10 –30% and ulcer development is highly dependent on intragastric pH. This double-blind, parallel-group, multicenter study evaluated the effect of esomeprazole over 6 months compared with placebo for ulcer prevention, in high risk patients receiving daily NSAID therapy. Methods: We studied 585 H. pylori-negative patients (ⱖ18 y), who had taken non-selective or COX-2 selective NSAIDs for ⱖ4 weeks. The patients had no current GU and/or DU, but were at increased ulcer risk because of age ⱖ60 years and/or a recent (5 yr) GU and/or DU. The patients were randomized to receive esomeprazole 40 mg (E40), 20 mg (E20) or placebo qd for 6 months and underwent endoscopy and upper GI symptom evaluation by the investigator at baseline and after 1, 3 and 6 months. The primary endpoint was the proportion of patients who developed a gastric or duodenal ulcer over 6 months. The proportion of patients with resolved upper GI symptoms (rating of none for the past 7 days on a 4 point scale from none to severe) was also evaluated at 6 months in users of both non-selective and COX-2 selective NSAIDs. Results: E40 mg and E20 mg treatment reduced the rate of ulcer recurrence by 64.2% and 57.7% overall vs placebo at 6 months (Table). On esomeprazole, patients were more likely to be without heartburn (E40: 76.2%; E20: 80.5% vs 63.2% on placebo, p⫽0.0022 and p⫽0.0002) and acid regurgitation (E40: 79.2%; E20: 85.4% vs 66.2% on placebo, p⫽0.0096 and p⬍0.0001) at 6 months. A Life Table estimate of the proportion of patients developing ulcers by 6 months (ITT population) E40 n COX-2 selective NSAIDs Non-selective NSAIDs Total

29

Life Table rate (95% CI) 0%

167 5.1% (1.7–8.6)

E20 n 24

Placebo

Life Table rate (95% CI)

Life Table rate (95% CI)

0%

19.1% (5.3–33.0)

168 5.9% (2.2–9.7)

10.6% (5.3–15.8)

196 4.4% (1.4–7.4)***192 5.2% (1.9–8.5)** 12.3% (7.2–17.4)

***p⫽0.008 vs placebo, **p⫽0.018 vs placebo; log rank test

Conclusions: Esomeprazole 40 mg and 20 mg treatment significantly reduced the development of gastroduodenal ulcers and associated upper GI symptoms in high risk patients using non-selective or COX-2 selective NSAIDs. 149 INCIDENCE OF ENDOSCOPIC GASTRODUODENAL ULCERS(GDUS) IN THE PLACEBO ARMS IN RANDOMIZED CONTROLLED NSAIDS TRIALS-—A META-ANALYSIS Yuhong Yuan, Ph.D., Jiaqing Huang, M.D., ChangCheng Wang, M.D., Richard H. Hunt, FACG*. McMaster University Medical Centre, Hamilton, ON, Canada.

Purpose: The safety of NSAIDs in the gastrointestinal (GI) tract is often evaluated by comparison with placebo in clinical trials. The incidence rate of GDUs in the placebo arm may influence the interpretation of the relative safety of an NSAID. We aimed to study the rate of GDUs over time in NSAID trials over the last 3 decades. Methods: Randomized placebo-controlled trials of NSAIDs from 1975 to 2003 were systematically reviewed. Trails required endoscopy was performed before randomization and after treatment. Results: 31 studies met inclusion criteria with treatment durations of 1–24 weeks. By ITT analysis, 3.85% (81/2189) GDU reported in placebo treated subjects 31 arms) in past 28 years. Rates of GDU in placebo arms were 0(0/83), 3.88% (49/1263) and 3.80% (32/843) in studies 1975–1987, 1990 –1999, and 2000 –2003 respectively (p⬎0.05). In the univariate analysis of studies after 1990, the pooled endoscopic GDU rate in the placebo arms was significantly higher in studies where the mean age was ⱖ60 (5.43% vs 2.12%); with therapy duration ⱖ4 weeks (4.10% vs 1.17%); in OA/RA patients (5.46% vs 1.32%); eligible patients with previous peptic ulcer (4.10% vs 0.99%); subjects with ⱕ10 mucosa erosions at baseline endoscopy (4.69% vs 1.79%) (pⱕ0.01).There was higher but not significant GDU rate in placebo arms in studies permitted cotherapy with low dose aspirin (ⱕ325mg/d) and NSAID (but not placebo) or corticosteroids (ⱕ10mg/d) than in those with no cotherapy (3.79% vs 1.79%, p⫽0.63). From 1990, 9.17% (642/7003) subjects receiving any antiinflammatory drugs (non-aspirin non-selective NSAIDs (NANSAIDs) or COX-2 preferential/selective inhibitors (coxibs) ) developed endoscopic ulcers. In total, the incidence of endoscopic GDU in the NANSAIDs arms (15.1%) were significantly higher than the placebo arms (3.85%) and coxib arms (4.48%) (p⬍0.0001). The incidence of GDU in the coxib arms was not significantly higher than placebo (p⫽0.55). Conclusions: The endoscopic GDU rate in placebo subjects has not changed over the last 3 decades; more high risk populations participated in NSAIDs trials. NANSAIDs produced significantly higher ulcer rates than placebo or coxibs. The ulcer rate on coxibs was similar to placebo, regardless of risk factors. GDU rates are likely to decline with increasing clinical use of coxibs for high risk patients, who are less likely to be entered into clinical trials against non-selective NSAIDs.

150 MALROTATION OF GASTRIC FUNDUS IS A CAUSE OF FUNCTIONAL DYSPEPSIA; ENDOSCOPIC GASTROPEXY IS AN EFFECTIVE TREATMENT William Y. Chey, M.D., D.Sc.*, George Y. Kunze, M.D., Katherine L. Fulton, R.N., Janice A. Haller, P.A., K. Alexandria Silvernail, N.P., Kae Y. Lee, M.D. Rochester Institute for Digestive Diseases and Sciences, Rochester, NY. Purpose: In 2 patients with malrotation of gastric fundus, surgical gastropexy relieved their severe dyspepsia. We have investigated the efficacy of endoscopic gastropexy on functional dyspepsia (FD) in patients with fundic malrotation or deformity. Methods: In 300 H. Pylori-negative patients with functional dyspepsia (FD) resistant to PPI, GI fluoroscopy was performed during and after liquid barium and cooked ground beef patty, using a portable C-arm fluoroscopic equipment (Philips). Seventy three (50F/23M, 18 – 82 yrs), showed a partial malrotation and/or angulation of the fundus. Twenty (9F/11M, 18 – 82 yrs) had gastropexy; 3, surgical gastropexy; 1, surgical gastropexy followed by endoscopic gastropexy and 16 with endoscopic gastropexy. During endoscopic gastropexy procedure, fundic deformity was endoscopically corrected and a PEG tube was placed in anterior wall of distal fundus via mid-epigastric wall to attach gastric wall to abdominal wall. The tube was removed in 6 weeks. Results: All tolerated gastropexy well. F/U fluoroscopies confirmed correction of the deformity. Symptom scores (1 to 5) for pain, belching, heartburn, bloating, nausea, vomit, and early satiety before and after 1 to 2