Clinical Challenges in Upper Gastrointestinal Disorders
Clinical Challenges in Upper Gastrointestinal Disorders
New Orleans, Tuesday, May 18, 2004 -- Topics in esophageal disease were once again the focus of insightful discussion at the Digestive Disease Week (DDW) meeting. This was perhaps best reflected by the clinically important studies presented during the American Gastroenterological Association Distinguished Abstract Plenary Session on Esophageal, Gastric, and Duodenal Disorders. This report explores some of the more key presentations focusing on various aspects of upper gastrointestinal disorders, as discussed during this session.
Ulceration Related to Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the United States. Approximately 15-25 million patients use NSAIDs on a regular basis. One percent to 3% of patients develop serious gastrointestinal complications associated with NSAID therapy. In this setting, several studies have addressed measures to reduce the risk of gastrointestinal ulceration and gastrointestinal bleeding. Omeprazole coadministered with a nonselective anti-inflammatory drug (eg, naproxen) has been shown to prevent ulceration and to heal ulcers. In patients who develop ulcers, omeprazole healed ulcers and prevented recurrent ulceration at the same rate as misoprostol, but there were fewer side effects with omeprazole. Cyclooxygenase (COX)-2 selective inhibitors have been shown to reduce the rate of ulceration compared with nonselective NSAIDs, and have been shown to decrease rates of gastrointestinal bleeding and perforation -- but these complications are not entirely prevented. In patients with arthritis and NSAID-related ulcer bleeding, a randomized controlled trial of omeprazole plus diclofenac was compared with celecoxib, a COX-2-selective inhibitor. The regimens were equivalent in preventing recurrent bleeding. COX-2 inhibitors are more costly than nonselective agents, and dyspeptic symptoms are as common in patients taking COX-2 inhibitors as they are in patients taking nonselective agents.
Preliminary data presented at this year's DDW meeting suggested that esomeprazole decreased dyspeptic symptoms in patients taking nonselective and COX-2 inhibitors. Scheiman and colleagues presented the results of 2 randomized placebo-controlled, parallel-group, multicenter studies of similar design to determine whether esomeprazole 20 mg or 40 mg prevented the development of gastric or duodenal ulcers in at-risk patients (individuals older than 60 years of age with a history of ulceration). Patients underwent endoscopy at baseline, 1 month, 3 months, and 6 months. There were 452 patients in the placebo group (ulcer incidence at 6 months = 17%), 459 patients in the esomeprazole 20-mg group (ulcer incidence 5.2%; P < .001 compared with placebo), and 467 patients in the esomeprazole 40-mg group (ulcer incidence 4.6%; P < .001 compared with placebo). In the subgroup of patients taking COX-2-selective inhibitors, 134 were randomized to placebo, with an ulcer incidence of 16.5%. One hundred twenty-five patients were in the esomeprazole 20-mg group, with an ulcer incidence of 0.9% (P < .001 compared with placebo). Finally, there were 141 patients in the esomeprazole 40-mg group, with an ulcer incidence of 4.1% (P < .001 compared with placebo). In the nonselective subgroup, the ulcer incidence was 17.1% among patients receiving placebo (n = 318), 6.8% among patients receiving esomeprazole 20 mg (n = 334), and 4.8% among patients receiving esomeprazole 40 mg (n = 326). The results of this study show that therapy with esomeprazole prevented ulcers in patients taking nonselective and COX-2-selective agents. Another important finding was that the ulcer incidence in the placebo group was similar among patients taking nonselective and selective agents. These data suggest that acid inhibition is effective in reducing ulcer rates in patients taking COX-2-selective NSAIDs as well as in patients taking nonselective agents.
pH Testing on Proton-Pump Inhibitor Therapy
pH testing is frequently performed in patients taking proton-pump inhibitors (PPIs). However, there is little information regarding the utility of this technique in clinical practice. Some studies have suggested that a substantial number of patients with symptoms resistant to single daily PPI therapy have uncontrolled reflux. Amin and colleagues showed that acid laryngopharyngeal reflux was common (56%) in patients receiving single-daily-dose therapy with PPIs. Other studies have shown that persistent acid reflux is common in patients with Barrett's esophagus who are on PPI therapy.
During this year's meeting proceedings, Vaezi and colleagues presented data from a retrospective review of 2291 ambulatory pH recordings. Patients were classified as typical (heartburn and regurgitation) or atypical (chest pain, cough, hoarseness, sore throat, shortness of breath, asthma) based on gastroesophageal reflux disease (GERD) symptoms. Two hundred fifty patients receiving either daily or twice-daily PPI therapy underwent pH monitoring; 115 (46%) patients had atypical GERD and 135 (54%) had typical GERD. Abnormal pH tracings were 3 times higher for patients tested on daily PPIs (odds ratio [OR] = 3.33; 95% confidence interval [CI] = 1.87-5.92; P < .01), whereas the odds of a normal pH value were 11 times higher for patients on twice-daily PPI therapy (OR = 11.11; 95% CI = 4.17-25.0; P < .01). Eighty-two of 119 (69%) patients tested on daily PPI therapy, and 126 of 131 (96%) patients on twice-daily PPIs tested normal (P < .01). A cost analysis (manometry plus pH monitoring) revealed an overall expenditure of $125,600 for typical and $75,000 for atypical GERD patients, with no additional diagnostic yield. The study authors concluded that the likelihood of an abnormal esophageal pH reading for symptomatic GERD patients on twice-daily PPI therapy is quite small. In atypical GERD patients who remain symptomatic, performing pH monitoring while on therapy is costly with no additional diagnostic yield. Further prospective studies are warranted to determine the utility of pH testing in patients on PPI therapy.
Dyspepsia and the Test-and-Treat Strategy
The test-and-treat strategy for Helicobacter pylori has been shown to be cost-effective in the management of dyspeptic patients in the primary-care setting. Lassen and colleagues randomized 500 dyspeptic patients in primary care to either H pylori test-and-treat or prompt endoscopy. They found that there were no differences in symptomatic outcomes or quality of life between the 2 groups at 1 year, although the endoscopy group had a slightly higher patient satisfaction score of uncertain significance. Similar data have been reported by other groups.
During this year's scientific session, Lassen and colleagues presented data from a long-term follow-up of the subjects in their original study. Symptoms, quality of life, and patient satisfaction were recorded during a 3-month period at a median of 6.7 years after randomization (range, 6.1-7.3 years). The rate of endoscopy, use of antisecretory medication, and H pylori treatment were recorded from healthcare databases for the entire follow-up period. The primary study endpoint was the proportion of days without dyspeptic symptoms reported in symptom diaries recorded 1 week during each of the 3 months. There was no difference in symptoms between the 2 groups. There was no significant difference in the number of symptom-free days between the groups, nor was there any difference in quality of life, patient satisfaction, number of sick-leave days, or visits to the general practitioner. The application of endoscopy in the test-and-eradicate group was 41% less than in the early (prompt) endoscopy group. The use of antisecretory therapy in the test-and-eradicate group was lower than in the endoscopy group, and the use of eradication treatments was higher. During follow-up, 2 patients in the test-and-eradicate group had bleeding peptic ulcer; both were NSAID-related. Thus, the test-and-eradicate strategy is effective over the long term and is associated with a reduction in the need for endoscopy and antisecretory therapy.
Other Studies of Interest
Transmission routes of H pylori are poorly defined, although a number of investigations have suggested some form of familial acquisition. A study from rural Africa suggested that H pylori transmission may be related to horizontal spread in siblings and housemates rather than to mother-child relationships, as other studies have suggested. These findings emphasize the dilemma of explaining both the high rate of recombination in H pylori and the presence of a single persistent H pylori genotype in most afflicted individuals.
In another study, Caviglia and colleagues confirmed earlier reports indicating that patients with nonerosive reflux disease have dilated intercellular spaces on transmission electron microscopy. The association between typical GERD symptoms and esophageal acid exposure is poorly defined. Dilation of intercellular spaces of esophageal epithelium serves as a morphologic marker of tissue damage and has been demonstrated in patients with both erosive and nonerosive GERD with an abnormal pH profile.
Concluding Remarks
Approaches to the management of upper gastrointestinal disorders continue to evolve. It is hoped that the above discussion helps to place some of the more topical issues in a clinically practical and relevant context.
References
New Orleans, Tuesday, May 18, 2004 -- Topics in esophageal disease were once again the focus of insightful discussion at the Digestive Disease Week (DDW) meeting. This was perhaps best reflected by the clinically important studies presented during the American Gastroenterological Association Distinguished Abstract Plenary Session on Esophageal, Gastric, and Duodenal Disorders. This report explores some of the more key presentations focusing on various aspects of upper gastrointestinal disorders, as discussed during this session.
Ulceration Related to Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the United States. Approximately 15-25 million patients use NSAIDs on a regular basis. One percent to 3% of patients develop serious gastrointestinal complications associated with NSAID therapy. In this setting, several studies have addressed measures to reduce the risk of gastrointestinal ulceration and gastrointestinal bleeding. Omeprazole coadministered with a nonselective anti-inflammatory drug (eg, naproxen) has been shown to prevent ulceration and to heal ulcers. In patients who develop ulcers, omeprazole healed ulcers and prevented recurrent ulceration at the same rate as misoprostol, but there were fewer side effects with omeprazole. Cyclooxygenase (COX)-2 selective inhibitors have been shown to reduce the rate of ulceration compared with nonselective NSAIDs, and have been shown to decrease rates of gastrointestinal bleeding and perforation -- but these complications are not entirely prevented. In patients with arthritis and NSAID-related ulcer bleeding, a randomized controlled trial of omeprazole plus diclofenac was compared with celecoxib, a COX-2-selective inhibitor. The regimens were equivalent in preventing recurrent bleeding. COX-2 inhibitors are more costly than nonselective agents, and dyspeptic symptoms are as common in patients taking COX-2 inhibitors as they are in patients taking nonselective agents.
Preliminary data presented at this year's DDW meeting suggested that esomeprazole decreased dyspeptic symptoms in patients taking nonselective and COX-2 inhibitors. Scheiman and colleagues presented the results of 2 randomized placebo-controlled, parallel-group, multicenter studies of similar design to determine whether esomeprazole 20 mg or 40 mg prevented the development of gastric or duodenal ulcers in at-risk patients (individuals older than 60 years of age with a history of ulceration). Patients underwent endoscopy at baseline, 1 month, 3 months, and 6 months. There were 452 patients in the placebo group (ulcer incidence at 6 months = 17%), 459 patients in the esomeprazole 20-mg group (ulcer incidence 5.2%; P < .001 compared with placebo), and 467 patients in the esomeprazole 40-mg group (ulcer incidence 4.6%; P < .001 compared with placebo). In the subgroup of patients taking COX-2-selective inhibitors, 134 were randomized to placebo, with an ulcer incidence of 16.5%. One hundred twenty-five patients were in the esomeprazole 20-mg group, with an ulcer incidence of 0.9% (P < .001 compared with placebo). Finally, there were 141 patients in the esomeprazole 40-mg group, with an ulcer incidence of 4.1% (P < .001 compared with placebo). In the nonselective subgroup, the ulcer incidence was 17.1% among patients receiving placebo (n = 318), 6.8% among patients receiving esomeprazole 20 mg (n = 334), and 4.8% among patients receiving esomeprazole 40 mg (n = 326). The results of this study show that therapy with esomeprazole prevented ulcers in patients taking nonselective and COX-2-selective agents. Another important finding was that the ulcer incidence in the placebo group was similar among patients taking nonselective and selective agents. These data suggest that acid inhibition is effective in reducing ulcer rates in patients taking COX-2-selective NSAIDs as well as in patients taking nonselective agents.
pH Testing on Proton-Pump Inhibitor Therapy
pH testing is frequently performed in patients taking proton-pump inhibitors (PPIs). However, there is little information regarding the utility of this technique in clinical practice. Some studies have suggested that a substantial number of patients with symptoms resistant to single daily PPI therapy have uncontrolled reflux. Amin and colleagues showed that acid laryngopharyngeal reflux was common (56%) in patients receiving single-daily-dose therapy with PPIs. Other studies have shown that persistent acid reflux is common in patients with Barrett's esophagus who are on PPI therapy.
During this year's meeting proceedings, Vaezi and colleagues presented data from a retrospective review of 2291 ambulatory pH recordings. Patients were classified as typical (heartburn and regurgitation) or atypical (chest pain, cough, hoarseness, sore throat, shortness of breath, asthma) based on gastroesophageal reflux disease (GERD) symptoms. Two hundred fifty patients receiving either daily or twice-daily PPI therapy underwent pH monitoring; 115 (46%) patients had atypical GERD and 135 (54%) had typical GERD. Abnormal pH tracings were 3 times higher for patients tested on daily PPIs (odds ratio [OR] = 3.33; 95% confidence interval [CI] = 1.87-5.92; P < .01), whereas the odds of a normal pH value were 11 times higher for patients on twice-daily PPI therapy (OR = 11.11; 95% CI = 4.17-25.0; P < .01). Eighty-two of 119 (69%) patients tested on daily PPI therapy, and 126 of 131 (96%) patients on twice-daily PPIs tested normal (P < .01). A cost analysis (manometry plus pH monitoring) revealed an overall expenditure of $125,600 for typical and $75,000 for atypical GERD patients, with no additional diagnostic yield. The study authors concluded that the likelihood of an abnormal esophageal pH reading for symptomatic GERD patients on twice-daily PPI therapy is quite small. In atypical GERD patients who remain symptomatic, performing pH monitoring while on therapy is costly with no additional diagnostic yield. Further prospective studies are warranted to determine the utility of pH testing in patients on PPI therapy.
Dyspepsia and the Test-and-Treat Strategy
The test-and-treat strategy for Helicobacter pylori has been shown to be cost-effective in the management of dyspeptic patients in the primary-care setting. Lassen and colleagues randomized 500 dyspeptic patients in primary care to either H pylori test-and-treat or prompt endoscopy. They found that there were no differences in symptomatic outcomes or quality of life between the 2 groups at 1 year, although the endoscopy group had a slightly higher patient satisfaction score of uncertain significance. Similar data have been reported by other groups.
During this year's scientific session, Lassen and colleagues presented data from a long-term follow-up of the subjects in their original study. Symptoms, quality of life, and patient satisfaction were recorded during a 3-month period at a median of 6.7 years after randomization (range, 6.1-7.3 years). The rate of endoscopy, use of antisecretory medication, and H pylori treatment were recorded from healthcare databases for the entire follow-up period. The primary study endpoint was the proportion of days without dyspeptic symptoms reported in symptom diaries recorded 1 week during each of the 3 months. There was no difference in symptoms between the 2 groups. There was no significant difference in the number of symptom-free days between the groups, nor was there any difference in quality of life, patient satisfaction, number of sick-leave days, or visits to the general practitioner. The application of endoscopy in the test-and-eradicate group was 41% less than in the early (prompt) endoscopy group. The use of antisecretory therapy in the test-and-eradicate group was lower than in the endoscopy group, and the use of eradication treatments was higher. During follow-up, 2 patients in the test-and-eradicate group had bleeding peptic ulcer; both were NSAID-related. Thus, the test-and-eradicate strategy is effective over the long term and is associated with a reduction in the need for endoscopy and antisecretory therapy.
Other Studies of Interest
Transmission routes of H pylori are poorly defined, although a number of investigations have suggested some form of familial acquisition. A study from rural Africa suggested that H pylori transmission may be related to horizontal spread in siblings and housemates rather than to mother-child relationships, as other studies have suggested. These findings emphasize the dilemma of explaining both the high rate of recombination in H pylori and the presence of a single persistent H pylori genotype in most afflicted individuals.
In another study, Caviglia and colleagues confirmed earlier reports indicating that patients with nonerosive reflux disease have dilated intercellular spaces on transmission electron microscopy. The association between typical GERD symptoms and esophageal acid exposure is poorly defined. Dilation of intercellular spaces of esophageal epithelium serves as a morphologic marker of tissue damage and has been demonstrated in patients with both erosive and nonerosive GERD with an abnormal pH profile.
Concluding Remarks
Approaches to the management of upper gastrointestinal disorders continue to evolve. It is hoped that the above discussion helps to place some of the more topical issues in a clinically practical and relevant context.
References
Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338:719-726.
Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998;338:727-734.
Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-1528
Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002;347:2104-2110.
Scheiman J, Vakil N, Hawkey C, et al. Esomeprazole prevents gastric and duodenal ulcers in at-risk patients on continuous non-selective or COX-2-selective NSAID therapy. Gastroenterology. 2004;126(suppl 2):A-82. [Abstract 638]
Amin MR, Postma G, Johnson P, Digges N, Koufman J. Proton pump inhibitor resistance in the treatment of laryngopharyngeal reflux. Otolaryngol Head Neck Surg. 2001;125:374-378.
Basu K, Bale R, West K, de Caestecker J. Persistent acid reflux and symptoms in patients with Barrett's esophagus on proton pump inhibitor therapy. Eur J Gastroenterol Hepatol. 2002;14:1187-1192.
Vaezi M, Charbel S. On-therapy pH monitoring: usually recommended but should we do it? Gastroenterology. 2004;126(suppl 2):A-82. [Abstract 640]
Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradication versus prompt endoscopy for management of dyspepsia patients: a randomised trial. Lancet. 2000;356:455-460.
Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC. A prospective randomised trial of a "test and treat" policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut. 1999;45:186-190.
Lassen A, Hallas J, Schaffalitzky de Muckadell O. Helicobacter pylori Test-and-eradicate vs. prompt endoscopy for management of dyspeptic patients in primary care: 6.7 years follow-up of a randomized trial. Gastroenterology. 2004;126(suppl 2):A-83. [Abstract 643]
Van der Merwe S, Cunningham M, Preisig O, Olivier B. A population genetics pedigree perspective on familial transmission of Helicobacter pylori. Gastroenterology. 2004;126(suppl 2):A-82. [Abstract 641]
Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces in non erosive reflux disease patients with physiological esophageal acid exposure. Gastroenterology. 2004;126(suppl 2):A-82. [Abstract 642]
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