Managing Acid-related Disorders Through the Ages of Mankind

At an industry-sponsored symposium held in conjunction with the American College of Gastroenterology’s 2002 Annual Scientific Meeting, a panel of experts reviewed the latest advances in anti-secretory therapy for children and evaluated long-term treatment options for adults with chronic gastroesophageal reflux disease.

In addition, the panel considered the evidence supporting the appropriate use of anti-inflammatory agents plus a proton pump inhibitor to reduce gastrointestinal injury in patients requiring anti-inflammatory analgesia or aspirin for cardiovascular prophylaxis.

This program was sponsored by CME Consultants, Inc. This program was supported by TAP Pharmaceutical Products, Inc.

This material represents a compilation from a series of industry-sponsored educational symposia presented October 18–23, 2002 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient.

The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.

The Pediatric Patient with Esophagitis

Children with gastroesophageal reflux (GER) may not be diagnosed until they present with a complication of gastroesophageal reflux disease (GERD), reported Harland S. Winter, MD, Director of the Pediatric Inflammatory Bowel Disease Center at Massachusetts General Hospital in Boston, Massachusetts. In contrast, over 50% of infants less than 6 months of age regurgitate, but symptoms resolve spontaneously in 95% of these patients. Among adolescents, the prevalence of GER is approximately 7%. How many children with symptoms of reflux progress to become adults with complications of GERD is not known.

Clinical Symptoms of Pediatric GER and Predisposing Conditions
Common clinical symptoms in children younger than 2 years of age include regurgitation, irritability, vomiting, and coughing. In full-term infants, regurgitation usually resolves by 12-15 months of age. As in the adult population, older children and adolescent patients with GERD may exhibit regurgitation, heartburn, epigastric pain, and wheezing
(Table 1).

Neurologic impairment, repaired tracheoesophageal fistula, or previous esophageal surgery in children predispose them to delayed acid clearance and motility disorders. Prematurity or bronchopulmonary dysplasia also may contribute to pediatric reflux. GERD or symptoms of dysphagia associated with obesity, cystic fibrosis, adenoid hyperplasia, and asthma may begin in childhood and often persist into adulthood.

Diagnostic Tests for Pediatric Reflux
Upper gastrointestinal X-rays are an important aspect of the evaluation of a child with GERD and are useful in detecting anatomic abnormalities. pH-probe testing is used to examine the relationship between GER and meals, activities, or sleep. Biopsies of the esophagus, stomach, and duodenum may assist in determining whether symptoms are related to GER or to eosinophilic esophagitis, and to identify inflammation or infection. Esophageal motility is most important when considering fundoplication or primary esophageal motility disorders such as achalasia. Determination of gastric emptying may be valuable in assessing children with food allergies or global motility disorders in which reflux is related to delayed gastric emptying.

Management Options for Pediatric GERD
The H₂ antagonists nizatidine and cimetidine are effective in healing erosive esophagitis in pediatric patients over 8 and 12 weeks, but are not as effective as proton pump inhibitors (PPIs), stated Dr. Winter (Simeone D, et al. J Pediatr Gastroenterol Nutr. 1997;25:51; Cucchiara S, et al. J Pediatr Gastroenterol Nutr. 1989;8:150). In a recent report, Tolia et al have found that the efficacy of lansoprazole in children and adults is similar in terms of reducing both GERD symptoms and the number of days with symptoms (Tolia V, et al. J Pediatr Gastroenterol Nutr. 2002;35: S308). In addition, all PPIs tested in children also achieved similar esophageal healing rates to those obtained in adults (Hassall E, et al. J Pediatr. 2000;137:800; Huang JQ, et al. Gut. 1999;45:140).

An advantage of PPI capsules is that they may be opened and the contents may be added to juice or applesauce. This increases compliance among children who cannot swallow capsules or tablets, reported Dr. Winter. Lansoprazole is currently available in a strawberry-flavored liquid suspension and other formulations of lansoprazole and omeprazole also are appropriate for pediatric use. Fast-dissolve and intravenous preparations are being developed. These formulations will enable children who cannot swallow pills to have access to a class of medications that appear to be safe and effective for the treatment of a chronic disease that for many adults begins in childhood and progresses throughout their lives.

The quality of life is substantially reduced in patients with erosive and nonerosive reflux disease, and work productivity decreases as the severity of heartburn increases (Wahlqvist P, et al. Am J Gastroenterol. 2001;96:S57), observed Richard H. Hunt, FRCP, FRCP(C), FACG, Professor of Medicine and Director of the Intestinal Disease Research Unit, and of the Division of Gastroenterology at McMaster University Medical Centre in Hamilton, Ontario. Dr. Hunt reviewed various management options for adults with persistent reflux symptoms.

Medical Management of Adults With Persistent Symptoms of GERD
One research report that was cited has concluded that both 30 mg QD and 15 mg QD doses of the proton pump inhibitor (PPI) lansoprazole were significantly (P<0.001) more effective than the H₂-receptor antagonist ranitidine 300 mg BID at maintaining remission in patients with GERD over 1 year (Gough AL, et al. Aliment Pharmacol Ther. 1996;10:529). In maintenance trials of patients with erosive esophagitis, lansoprazole 15 mg QD and 30 mg QD and omeprazole 20 mg QD consistently achieved 12-month remission rates of 70%-90%, whereas daily doses of ranitidine 300 mg and 600 mg produced remission rates of 15%-30% (Figure 1) (Freston JW, et al. Drugs. 2002;62:1173). Moreover, Klinkenberg-Knol et al showed that in patients with reflux, the required dose and therapeutic benefit of omeprazole remained remarkably consistent over a 10-year treatment period (Klinkenberg-Knol EC, et al. Gastroenterology. 2000;118:661).

Patients need to be informed of the proper time at which to take their PPI dose, recommended Dr. Hunt. Because of their short plasma half-life, PPIs must be taken on an empty stomach 1 hour before breakfast. If symptoms persist, patients should take a second dose on an empty stomach 1 hour before dinner and have nothing to eat or drink after the end of the meal before retiring to bed. Intra-esophageal pH monitoring may be required if symptoms do not resolve. Dr. Hunt stated that maintenance therapy with PPIs is safe, noting over 16 years of worldwide experience with these agents.

Surgical Treatment of Adults With Persistent Symptoms of GERD
In >85% of patients undergoing surgery for GERD, laparoscopic fundoplication is reported to be successful in controlling acid/bile reflux and regurgitation, although careful patient selection and surgical expertise are critical to this success (Kahrilas PJ. Am J Gastroenterol. 1999; 94:1721). Laparoscopic fundoplication is associated with a 9% complication rate and dysphagia in 5% of patients (Kahrilas PJ. Am J Gastroenterol. 1999;94:1721).

A survey of outcomes of laparoscopic surgery in community practice found that 46% of patients underwent surgery because of inadequate relief with medications (Vakil NB, et al. Gastroenterology. 2001;120:S1:A16); 17% were concerned about possible long-term adverse effects of PPIs; and 10% were hoping that surgery would prevent cancer. Although 58% of patients were satisfied with the surgical outcome, 67% experienced new symptoms of dysphagia, bloating, or gas, and 27% were still taking medications for GERD. A further study of 2,383 patients who underwent anti-reflux surgery also showed that 34% and 23% required PPI and H2 antagonist therapy, respectively, 6 months after surgery (DiRe, et al. Gastroenterology. 2002;122:A75).

Reviewing endoscopic approaches to managing chronic reflux, Dr. Hunt referred to one of the procedures, which requires high doses of sedation. In addition, despite initial improvement in mean heartburn and quality of life scores, 30% of patients were still requiring a PPI at 12 months (Triadafilopoulos G, et al. Gastrointest Endosc. 2002;55:149). Similar results were found with the gastroplasty transoral technique (Rothstein, et al. Am J Gastroenterol. 2001;96: A107). General clinical application of these endoscopic approaches is therefore premature, believes Dr. Hunt.

Healing and Prevention of NSAID-associated Gastric Ulcers in Elderly Patients

One study has concluded that an estimated 10,000-16,000 people in the United States die each year as a result of gastrointestinal (GI) complications caused by nonsteroidal anti-inflammatory drugs (NSAIDs) (Singh G, et al. J Rheum. 1999;26:18), stated David A. Peura, MD, Professor of Medicine and Associate Chief of the Division of Gastroenterology and Hepatology at the University of Virginia School of Medicine at the University of Virginia Health Sciences Center in Charlottesville, Virginia. According to one estimate, a further 100,000 people are hospitalized every year for NSAID-related GI effects. Stratifying patients according to their risk can help to address this formidable problem, observed Dr. Peura.

Risk factors for NSAID-associated ulcer complications include a history of ulcers, the use of multiple and/or high-dose NSAIDs, anti-coagulation therapy, age >70 years, and the use of steroids. The risk of complications is greatest within the first 3 months of NSAID use. Interestingly, most patients who experience a serious NSAID-related GI event are asymptomatic before the event (Gabriel S, et al. Ann Intern Med. 1991;115: 787;Garcia Rodriguez L, et al. Lancet. 1994;343: 769; Silverstein F, et al. Ann Intern Med. 1995;123:241).

Management of NSAID-associated Ulcers
Proton pump inhibitors (PPIs) are more effective than H2-receptor antagonists in healing gastric and duodenal ulcers. In patients with NSAID-induced gastric ulcers who continued with their NSAID therapy, 15 mg QD and 30 mg QD doses of the PPI lansoprazole were significantly (P<0.05) more effective than the H₂-receptor antagonist ranitidine 150 mg BID in healing ulcers at 8 weeks (Agrawal N, et al. Arch Intern Med. 2000;160:1455). Likewise, omeprazole 20 mg QD achieved healing rates of 81% and 92% for NSAID-associated gastric and duodenal ulcers, respectively (P<0.001, and P = 0.03, respectively) (Yeomans N, et al. N Engl J Med. 1998;338:719).

Prevention of Ulcer Recurrence and Ulcer-associated Complications
In long-term users of NSAIDs, lansoprazole 15 mg QD and 30 mg QD were not only equivalent to misoprostol 200 µg QID in preventing ulcer recurrences, but also were better tolerated (Graham D, et al. Arch Intern Med. 2002;162: 169). Importantly, lansoprazole maintained its efficacy even in patients who were taking low-dose aspirin concomitantly with their NSAIDs, demonstrating that in patients taking an NSAID plus aspirin, PPIs can help to prevent recurrence of NSAID-associated gastric ulcers (Figure 1).

The impact of concomitant use of aspirin was reinforced in a recent trial of high-risk patients who had ulcer bleeding while they were taking aspirin for cardiovascular prophylaxis. After ulcer healing and eradication of Helicobacter pylori, patients who were randomized to lansoprazole 30 mg QD plus aspirin (100 mg/day) for 12 months had markedly reduced rates of bleeding ulcer recurrence compared with patients receiving only aspirin (Lai KC, et al. N Engl J Med. 2002;347;1623).

COX-2 Specific Inhibitors Versus Nonselective NSAIDs in Patients Taking Aspirin
Trials conducted in high-risk populations have examined the prevention of recurrent ulcer bleeding using cyclooxygenase-2 (COX-2) specific inhibitors versus a combination of a nonselective NSAID plus a PPI (Lai KC, et al. Gastroenterology. 2001;120:A104). No significant differences between the treatment arms were noted, which leads to the conclusion that the combination of a nonselective NSAID plus a PPI may be equivalent to a COX-2 specific inhibitor in preventing recurrence of NSAID-related ulcer complications, at least if the patient is not taking concomitant aspirin.

In outcomes trials of COX-2 specific inhibitors, the incidence of GI complications was lower with COX-2 specific agents compared with nonselective NSAIDs (Bombardier C, et al. N Engl J Med. 2000;343:1520). However, if patients also were using aspirin, the rates of adverse GI events were similar at 6 months for COX-2 specific agents and nonselective NSAIDs (Silverstein F et al. JAMA. 2000;284: 1247). Thus, some question the GI safety benefit of COX-2 specific inhibitors, and specifically whether it is attainable in patients using aspirin. Moreover, switching patients from a nonselective NSAID to a COX-2 specific inhibitor has not been associated with reductions in GI co-therapy or total utilization of GI healthcare resources (Laine L et al. Gastroenterology. 2002;122:A53).

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