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A Supplement to Family Practice Newsă SYMPOSIUM HIGHLIGHTS New Benchmarks in Acid-Related Disorders: A Debate With the Experts Held May 19, 2002, in San Francisco, Calif.

Introduction Use of Nonselective NSAIDs, Cyclooxygenase A message from Richard Inhibitors, and Proton Pump Inhibitors H. Hunt, FRCP, FRCP(C), FACG, professor of medicine, Treat With Nonselective NSAIDs plus PPIs Treat With Cyclooxygenase Inhibitors McMaster University According to Michael B. Kimmey,MD,professor of med- Randomized trials clearly show that coxibs are less likely than Medical Centre, Hamil- icine and director of gastrointestinal at the nonselective NSAIDs to be associated with GI ulcers and ul- ton, Ont., who moderat- University of Washington, Seattle, cyclooxygenase in- cer symptoms in patients who require long-term antiin- ed the live symposium hibitors (coxibs) are no safer than nonselective NSAIDs in flammatory therapy for chronic arthritis,according to Jay L. on which the four cases patients with arthritis who are already taking aspirin for its Goldstein, MD, professor of medicine and vice head for and eight point-counter- antiplatelet benefits. Moreover, proton-pump-inhibitor clinical affairs,department of medicine,the University of Illi- point editorials in this (PPI) therapy has been shown to attenuate the ulcer risk nois at Chicago. This coxib advantage may apply even to pa- supplement were based. associated with chronic aspirin or nonaspirin NSAIDs. tients who take low-dose aspirin for the prevention of car- Therefore, the patient in question should be treated with diovascular events. Such patients might also benefit from enchmarks in PROFESSOR RICHARD H. HUNT a PPI plus an economical nonselective NSAID. use of a PPI to circumvent aspirin-induced ulcers.Risk fac- medicine are The safety,reliability,and cost-effectiveness of aspirin as tors for NSAID-related ulcer complications include a history Bregularly reviewed and updated based on the an antiplatelet agent have made it almost universal ther- of ulcers or ulcer bleeding, increasing age, heart disease, and rapidly evolving clinical knowledge base.The effects of apy for patients with a history of transient ischemic attack use of anticoagulants or multiple high-dose NSAIDs. Our such change—stemming from advances in pharma- or coronary heart disease. In patient has or faces three of cotherapy,technology,and our understanding of disease addition, aspirin's irre- THE CONSULT these risk factors, which are pathophysiology—are especially important in the are- versible acetylation of cy- each associated with odds ra- na of acid-related disorders, of which we are seeing clooxygenase (COX)-1 al- ¼ A 62-year-old teacher with a family history of tios for NSAID-induced ul- dramatically increased case numbers. Their effective lows its antiplatelet effect to colon cancer and a possible ulcer disease cer complications ranging management on a national scale requires us to ensure last up to 5 days. The re- dating to age 30-40. from 1.8 to 13.5 (Lancet. that our standards for disease monitoring, prevention, versible COX inhibition of 1994;343:769-772, Ann In- and treatment are appropriate and effective. other nonselective NSAIDs ¼ Diagnosed with osteoarthritis, hypertension, tern Med.1995;123:241-249). At a continuing-education symposium held in San makes them shorter-lasting and recurrent transient ischemic attacks. “We know that the inter- Francisco on May 19, 2002, eight expert physician-sci- antiplatelet agents; coxibs do action between risk factors entists conducted a series of collegial and intellectually not prevent platelet aggre- ¼ Taking beta blockers for occasional angina pec- is synergistic, not merely ad- productive debates on four unsettled clinical and health- gation. Even low-dose as- toris as well as low-dose aspirin to prevent cere- ditive. So without doubt the policy issues now being considered in management of pirin therapy can raise the brovascular symptoms. patient is at high risk for upper-GI ulcers, gastroesophageal reflux disease, and risk of GI bleeding, espe- NSAID-related ulcer com- their sequelae. cially when taken with oth- plications,” said Dr. Gold- For each of the four debates, two discussants present- er nonselective NSAIDs (Am J Gastroenterol. stein.The use of low-dose aspirin alone increases the risk ed detailed cases for different sides of the issue at hand. 2000;95:2218-2224). The 50% of such bleeding that is of upper-GI bleeding two- to fourfold (BMJ. ¼ Should an arthritic patient with a history of coronary not ulcer related cannot be prevented (Gastroenterology. 1995;310:827-830). disease and cerebrovascular events, who is taking pro- 1992;103:862-869). On the other hand, the risk of upper- Endoscopy data and prospective trials suggest no such phylactic low-dose aspirin, receive a nonaspirin con- GI ulcer bleeding is greatly reduced when aspirin-induced elevated risk among patients taking coxibs. Dr. Goldstein's ventional NSAID plus a proton pump inhibitor (PPI) or ulcers are prevented, said Dr. Kimmey.“And the most ef- group and other research teams have documented place- a selective cyclooxygenase-2 inhibitor, with or without fective and tolerated way bolike endoscopic ulcer PPI? to do that is with a PPI.” rates in patients with os- ¼ Should a patient who is taking a PPI that provides In fact, PPIs have a teoarthritis taking coxibs as good control of reflux symptoms be advised number of important ben- compared with nonaspirin to proceed with endoscopic or surgical interventions? efits in patients who must NSAIDs. For example, a ¼ Should patients with erosive esophagitis be routinely take aspirin or other non- pooled analysis of blinded, screened for Barrett's ? selective NSAIDs. Ome- randomized trials showed ¼ Is endoscopy-negative reflux a functional disorder, or prazole 20 mg/day for 3 an ulcer-complication rate should treatment decisions assume it is part of the spec- months has been shown to of 1.96 (per 100 patient- trum of gastroesophageal reflux disease? reduce the frequency of years) for NSAIDs but We invite you to weigh the arguments and decide dyspeptic symptoms, the only 0.68 for valdecoxib what your positions might be. most common GI com- (Gastroenterology. 2002; plication of NSAIDs 122:A-344). MICHAEL B. KIMMEY, MD Continued on page 2 Continued on page 2 JAY L. GOLDSTEIN, MD

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2 SYMPOSIUM HIGHLIGHTS

Options in the Long-Term Maintenance of Gastroesophageal Reflux Disease

Endoscopic/Surgical Intervention sophageal junction.The procedure can re- Management on Long-Term PPI Therapy dosage increases (Gastroenterology. 2000; According to George Triadafilopoulos, MD, duce transient lower esophageal sphincter The patient in question is responding well 118:661-669). professor of medicine at Stanford Universi- relaxations by 50% and appears to improve to treatment with a PPI and, studies show, The PPI safety record is well established, ty School of Medicine and chief, section of symptoms of and regurgitation could well need continued medical therapy observed Dr.Howden. There is no convinc- gastroenterology, Palo Alto Veterans Affairs as well as quality-of-life scores (Gastrointest even if antireflux surgery were to be per- ing evidence that PPIs promote gastric car- Health Care System, Palo Alto, Calif., pa- Endosc. 2002;55:149-156). Data from pa- formed, according to Colin W. Howden, cinoids, atrophic gastritis, intestinal metapla- tients with reflux disease whose symptoms tients who had taken PPIs and then under- MD, FACG, professor of medicine, North- sia or gastric adenocarcinoma, clinically are well controlled by proton-pump-in- went the Stretta procedure show that over western University Feinberg School of important enteric infection, or impairment hibitor (PPI) therapy do not need endo- 12 months, 61% were Medicine, Chicago. of nutrient absorption; even some observa- scopic or surgical interventions. However, able to go off PPIs or THE CONSULT “We know that the tions that PPIs hinder vitamin B12 absorption those treatments should be offered to pa- use over-the-counter PPIs are very effective, do not suggest a need for long-term serum ¼ tients who still experience heartburn or re- drugs as needed. A 46-year-old sales manager and consistently so, at B12 monitoring (Drug Safety. 1999;20:195- gurgitation after treatment with PPIs. Endoscopic gastro- with a 5-year history of reflux healing erosive eso- 205, J Clin Gastroenterol. 2000;30:29-33, Ali- “With PPIs, we often expect that plication, also available esophagitis has good symptom phagitis, and that their ment Pharmacol Ther. 2000;14:651-668). esophagitis will be healed. But PPI therapy now, can improve control on a PPI. side effects are general- “These drugs have been subjected to for 6 weeks controls symptoms in only 80% symptoms by altering ly mild and self-limit- very intensive, careful study since they were of patients with erosive esophagitis,” said the mechanics of the ¼ Has seen advertisements for en- ing,”said Dr. Howden. introduced,” said Dr. Howden.“There are Dr. Triadafilopoulos (Can J Gastroenterol. gastroesophageal junc- doscopic/surgical interventions “Is the patient's eso- sometimes side effects, but I don't believe I 1997;11[Suppl B]:66B-73B).“Twenty per- tion. In a U.S. multi- for the management of gastro- phagitis healed? We have ever seen a patient who is absolutely cent of patients may still have symptoms, center trial, the proce- esophageal reflux disease. don't know without intolerant to PPIs.”Surgical intervention is mostly regurgitation. And it is symptoms dure was associated endoscopy, but in all sometimes recommended for patients who that determine whether they will be re- with significant de- ¼ Asks about the pros and cons probability it is.” respond poorly to PPI treatment. Howev- ferred to us for possible endoscopic or sur- creases in rates of of long-term PPI therapy as com- A multitude of pub- er, they are precisely the patients in whom gical therapy.” Non-PPI treatments might heartburn and regur- pared with the endoscopic/sur- lished studies show that it is best to avoid surgery. And whether be considered for patients who respond to gitation (Gastrointest gical interventions. PPIs can produce clin- surgery can live up to patient expectations PPIs but are concerned about long-term Endosc. 2001;53:416- ical and endoscopic re- is questionable. medical-therapy sequelae, or those who 422). Other data sug- missions over 6-12 In a review of laparoscopic surgery out- don't tolerate the drugs well. gest that about one-fourth of treated pa- months in patients with erosive esophagitis comes in 83 patients with reflux disease, the Endoscopic therapy should be the non- tients do not need to take PPIs and another (Aliment Pharmacol Ther. 1996;10:529-539, reasons for choosing surgery consisted of in- medical intervention of choice for patients 28% require only a half-dose of PPI thera- Gastroenterology.2000;118:661-669).A recent adequate symptom relief on medications in with uncontrolled symptoms, and those py (Am J Gastroenterol. 2001;96:A-107). review of trials that compared lansoprazole 46%, hope for surgical “cure” in 26%, and a with partially controlled Endoscopic injection with placebo, with histamine H2-receptor preference for avoiding long-term medica- symptoms who would like therapy,which may soon be antagonists in standard or tion in 7% (Gastroenterology. complete control but want FDA approved, consists of high dose, or with omepra- 2001;120[Suppl 1]:A-16). to avoid surgery.Two endo- injecting a biopolymer in zole found 12-month remis- But symptoms can persist scopic procedures are avail- an organic liquid vehicle at sion rates in the 80%-90% with surgery or new symp- able, and others are expect- the lower esophageal range, regardless of disease toms can appear, continued ed soon. Their risk of sphincter muscle.The low- severity before treatment medications are often re- complication is low: less viscosity solution precipi- (Drugs.2002;62:1173-1184). quired, and cure is unlikely, than 0.25%. tates into a spongy mass Although some patients noted Dr. Howden. “Some The Food and Drug Ad- that seems to increase may have progressive, recur- patients look for the quick ministration-approved Stret- sphincter pressure and re- rent reflux disease despite fix and believe that either ta procedure involves the duce reflux (Gastrointest En- PPI therapy, they are few, surgery or endoscopic treat- application of radio fre- dosc. 2002; 55:335-341). are often not good surgical ments will prevent the need quency energy in a ringlike GEORGE The best candidates for candidates, and sometimes to take medications.” fashion at the gastroe- TRIADAFILOPOULOS, MD Continued on page 3 can be managed with PPI COLIN W. H OWDEN, MD Continued on page 3

Kimmey - from page 1 with a coxib rather than another nonselec- Goldstein - from page 1 one high-risk factor (Gastroenterology. (Scand J Gastroenterol. 1996;31:753-758). tive NSAID? The well-recognized coxib More conclusively, in the randomized, 2001;120:A-105). “Gastric and duodenal ulcers heal with PPI benefit of fewer ulcer complications likely double-blind CLASS trial of nearly 8,000 pa- In the VIGOR study,about one-third of therapy even with continued NSAID use,” does not apply to patients already taking tients, celecoxib was associated with signifi- GI bleeds were not in the upper-GI tract, Dr. Kimmey said. “Recurrences are pre- low-dose aspirin. In the randomized, dou- cantly fewer symptomatic upper-GI ulcers and there was still a significant reduction in vented more effectively than with [hista- ble-blind Celecoxib Long-Term Arthritis and ulcer complications over 6 months than lower-GI bleeding events with the coxib as mine] H2-[receptor antagonist] blockers, Safety Study (CLASS), which compared a were nonselective NSAIDs ( JAMA. 2000; compared with the nonselective NSAID. and patient tolerance is greater than with coxib with nonselective NSAIDs in patients 284:1247-1255). About 22% of CLASS pa- Hematocrit and hemaglobin changes in misoprostol.” with osteoarthritis or rheumatoid arthritis, tients were on low-dose aspirin.The differ- the CLASS trial suggest that celecoxib was In a randomized study of patients with ulcer complications were indeed signifi- ence between celecoxib and NSAIDs was significantly less likely to promote small NSAID-related gastric ulcers who received cantly elevated among nonaspirin-NSAID even further enhanced when the aspirin bowel and colonic bleeding than were the lansoprazole 15 mg/day or 30 mg/day, users. But ulcer complications were statisti- nonusers were analyzed separately. nonselective NSAIDs ibuprofen and di- misoprostol 200 µg qid, or placebo, the PPI cally just as prevalent with celecoxib as with Similar findings emerged from the ran- clofenac.These complications are not pre- was significantly better than placebo and as nonselective NSAIDs among the one-fifth domized, controlled Vioxx Gastrointesti- ventable with a PPI. effective as the prostaglandin at healing the of patients already taking aspirin (JAMA. nal Outcomes Research (VIGOR) study Thus, in patients who are not taking as- ulcer and keeping the patient ulcer-free 2000;284:1247-1255). of patients with rheumatoid arthritis, none pirin but require an antiinflammatory,cox- over 12 weeks (Arch Intern Med. 2002; “Patients who require aspirin but must of whom were on low-dose aspirin (N ibs are less likely than nonselective NSAIDs 162:169-175). The adverse-event rate was take a nonselective NSAID or a coxib for os- Engl J Med. 2000;343:1520-1528). The to promote upper-GI ulcers or their com- about the same with lansoprazole as with teoarthritis may as well use the less-costly VIGOR trial also showed dramatically plications. For patients who must take placebo, but was elevated with misoprostol. nonselective NSAID,” said Dr. Kimmey.“A fewer upper-GI events with the coxib than chronic low-dose aspirin, said Dr. Gold- Even with the patient taking prophylac- PPI should be prescribed to reduce the risk with a nonselective NSAID among both stein, the addition of a PPI may be indicat- tic aspirin, why not treat the osteoarthritis of aspirin-induced ulcer complications.” ■ low-risk patients or patients with at least ed but the benefit is not proven. ■ TAP_pg1_pg3_FP_7_25R.qxd 7/25/2002 1:10 PM Page 3

SYMPOSIUM HIGHLIGHTS 3

Is Screening for Barrett’s Esophagus Necessary?

Good Evidence for Screening dure (Gastrointest Endosc. 2002;55:AB200), Screenings Not Cost-Effective esophagus, for those with There could be 1-1.5 million persons with the perceived financial burden of routine There is no convincing evidence that an en- high-grade dysplasia, an operative mortality Barrett's esophagus in the United States,if the screening does not seem quite as imposing. doscopic screening program for persons with of 0.4%, hospice and other special cancer estimated number of asymptomatic, undiag- Cost estimates of $450 per unsedated en- reflux disease, even if the technologic or care, and an adjustment for long-term mor- nosed cases is included, according to Roy doscopic screening procedure for Barrett's manpower needs could be met, would im- bidity associated with surgery.An estimated K.H.Wong,MD, FACG, professor of medi- esophagus combined with biopsy suggest a prove survival or quality of life, noted Dawn 39,000 cancer deaths would be prevented cine and director of the division of digestive price tag of $23,738 Provenzale,MD,associ- at a cost of $425,641 each. diseases, Uniformed Services University of per quality life-year ate professor and direc- A published cost-effectiveness model for the Health Sciences, Bethesda, Md. The saved (Gastroenterology. THE CONSULT tor of GI outcomes re- colon-cancer screening (Gastroenterology. technology needed to perform rapid, accu- 2001;120:A-2116). ¼ The policy committee of an search at Duke Univer- 1995;109:1781-1790), based on a 20-year rate, and economical Barrett's esophagus Even that cost is ex- HMO is assembling evidence for sity Medical Center, program for the same 10 million patients screening exists, while recent studies indi- ceedingly reasonable; and against the routine screening Durham, N.C. with GERD and a 6% lifetime risk of colon cate that patients’ high risk for adenocarci- but at $54 per en- for Barrett’s esophagus in pa- “A cost-effective cancer, points to a much lower cost per pre- noma can be identified by surrogate markers. doscopy, the prospect tients with erosive esophagitis. strategy must provide vented death. With screening based on “There has been a rising incidence of becomes much more an incremental benefit every 10 years at a cost of esophageal adenocarcinoma over the past attractive. that is worth the incre- $20.8 billion, 270,000 cancer deaths would 30 years,”said Dr.Wong.“If we are going to The size of the screened population also mental cost,”said Dr. Provenzale (Am J Gas- be prevented at a cost of $77,037 each. screen widely for Barrett's esophagus, it drives the program costs. “Five percent of troenterol. 1996;91:1488-1493). “And, we Were screening to be based on annual fecal would be extremely costly using conven- persons with Barrett's esophagus go on to have no data suggesting that a screening and occult blood testing and flexible sigmoi- tional endoscopic techniques.”The cost- develop high-grade dysplasia,and out of this surveillance program for high-risk patients doscopy every 5 years, at a cost of $44.5 effectiveness of screening, however, could 5%, few develop cancer. If we performed would be worth any additional benefit.” billion, 200,000 cancer deaths would be be enhanced by improved endoscopic surveillance on every person with Barrett's It may make more economic and health- prevented at $222,500 each.“Given the low technology. esophagus, the cost could policy sense to screen the cancer risk in patients with “Better visualization and be prohibitive,” said Dr. same patient population for Barrett's esophagus, screen- smaller scopes coming soon Wong. The identification colorectal cancer. Computer ing patients with GERD will allow us to perform of surrogate markers to cohort simulations, based on with the goal of reducing screening faster identify patients with an the literature and U.S.census mortality is not only un- without sedation at reduced increased risk of eso- data from persons aged 50 or proven, it's expensive,”said cost,”said Dr.Wong. phageal adenocarcinoma older with gastroesophageal Dr. Provenzale. Such pa- In a recent comparison of could dramatically lower reflux disease (GERD),were tients are more likely to two 4-mm-diameter endo- the number of persons conducted and interpreted develop colorectal cancer scopes, one a conventional who might require surveil- from the perspective of an than esophageal adenocar- fiberoptic device and the lance. Such markers could HMO (Am J Gastroenterol. cinoma, and colorectal other an investigational col- include histologic findings, 1999;94:2043-2053). cancer screening would be or-chip-based system, the flow cytometry findings in Among a projected 10 mil- expected to save more latter was superior at visual- ROY K.H. WONG, MD Barrett's epithelium (Am J lion individuals with GERD, DAWN PROVENZALE, MD lives at a lower cost per life izing Barrett's esophagus, Gastroenterol. 2000;95: the prevalence of Barrett's saved. erosions, and hiatal (Gastrointest En- 1669-1676),p53-protein staining (Am J Gas- esophagus was estimated at 537,000 or about Thus the screening program the HMO is dosc. 2002;55:AB93).Videoesophagoscopy troenterol. 2001;96:1355-1362), and scanning 5.4%.To identify those patients based on en- considering would not be deemed cost-ef- took an average of 1 minute to perform, as of the p53 gene to identify mutations and loss doscopic screening would cost about $6 bil- fective, particularly as compared with compared with 2 minutes with the fiberop- of heterozygosity (Am J Gastroenterol. lion at $600 per procedure—based on re- screening for colorectal cancer, which is a tic device. 2001;96:2839-2848). A combination of source use, not charges. more serious public health problem. The Esophagoscopy using a device that allows these techniques would overlook few pa- The cost of a 20-year program of surveil- identification of reliable high-risk indica- 60-second procedures could allow one per- tients at increased risk. lance—in this analysis, every 3 years—for tors for Barrett's esophagus and adenocarci- son to perform more than 20,000 screenings Thus,contemporary screening and surveil- the 537,000 persons at increased risk was noma in patients with GERD,and their use per year.With recent findings suggesting that lance procedures could help to prevent a great based on a 1.3 per 1,000 rate of complica- for narrowing the screening population, endoscopic screenings performed by nurse many cases of esophageal adenocarcinoma at tions from endoscopy,a 0.4% annual risk of could improve the potential impact of a practitioners might cost only $54 per proce- a cost that society is willing to accept. ■ adenocarcinoma in patients with Barrett's screening program. ■

This Symposium Highlights was supported by a traZeneca. Speakers' Bureau: AstraZeneca, Merck, Triadafilopoulos - from page 2 Howden - from page 2 restricted grant from TAP Pharmaceutical Prod- TAP, Wyeth. Dr. Kimmey and Dr. Provenzale have surgery are younger patients with persistent Endoscopic treatments, including the Stretta proce- ucts, Inc. The articles are based on presentations nothing to disclose. Dr. Richter-Consultant: As- symptoms being treated with PPIs, patients dure, have not been compared with PPIs in a randomized given at a continuing medical education sympo- traZeneca, TAP. Speakers' Bureau: AstraZeneca, sium held on May 19, 2002, in San Francisco, Janssen, TAP, Wyeth. Dr. Triadafilopoulos-Consul- who are PPI intolerant, and those with low- trial. And, in contrast to the abundant long-term safety Calif. It was produced by the medical education tant: Curon Medical Inc., TAP. Grant Support: As- er-esophageal sphincter incompetence, a and efficacy data available for PPIs from randomized, and business development department of Interna- traZeneca. Speakers' Bureau: AstraZeneca, Curon, large sliding hiatal hernia,recurrent progres- controlled trials of patients with a range of disease sever- tional Medical News Group. Neither the editor of Janssen, TAP, Wyeth. Equity: Curon. Dr. Wong- sive disease despite PPI therapy, and/or bile ities, outcomes for endoscopic therapies are derived ex- the publication nor the reporting staff contributed Grant Support: ACG, AstraZeneca, Janssen. reflux. Candidates should be made aware of clusively from short-term uncontrolled studies in pa- to its contents. the risks: Laparoscopic fundoplication is as- tients with mild disease. Moreover, the success of Writer: Steve Stiles. Designer: James Reinaker. Copyright 2002 International Medical News Group, sociated with a 0.2% mortality and a nonfa- endoscopic therapies is operator dependent, the proce- Faculty Disclosures: Prof. Hunt-Consultant: Abbott an Elsevier Science company. All rights reserved. Laboratories, Axcan Pharma Inc., AstraZeneca, No part of this publication may be reproduced or tal complication rate of about 9% (Am J Gas- dures can be technically demanding, and they require Merck & Co., Novartis Pharmaceuticals Corp., transmitted in any form, by any means, without pri- troenterol. 1999;94:1721-1723). prolonged sedation or anesthesia. A recent editorial re- Procter & Gamble Co., TAP Pharmaceutical Prod- or written permission of the Publisher. The opinions Fundoplication by experienced laparo- view concluded that their general clinical application is ucts, Inc. Investigator: Axcan, AstraZeneca, Mer- expressed in this supplement are those of the pre- scopic surgeons can control heartburn, re- premature (Gastrointest Endosc. 2001;53:541-545). ck, TAP. Dr. Chey-Consultant: AstraZeneca, TAP. senters and do not necessarily reflect the views of gurgitation, and even bile reflux in more “Endoscopic treatments at the moment have not been Grant Support: AstraZeneca. Speakers' Bureau: As- the sponsor or the Publisher. International Med- than 85% of cases.“It is a short procedure and adequately studied and should be confined to clinical traZeneca, Janssen Pharmaceutica, Inc., TAP. Dr. ical News Group will not assume responsibility for not technically challenging, involves a short studies at centers of excellence,” said Dr. Howden.The Goldstein-Consultant & Grant Support: As- damages, loss, or claims of any kind arising from traZeneca, Pharmacia Corp., Pfizer Inc., TAP. Dr. or related to the information contained in this pub- hospital stay, and the cosmetic result is patient in question appears to have good symptom con- Howden-Consultant: Prometheus, Takeda Pharma, lication, including any claims related to the prod- good,”said Dr. Triadafilopoulos. “The chal- trol with PPI therapy, and if symptom control should TAP. Investigator: TAP, Merck. Grant Support: As- ucts, drugs, or services mentioned herein. lenge: selecting appropriate patients.” ■ ever become suboptimal,“we can increase the dose.” ■ TAP_IM_7_22_02.qxd 7/23/2002 8:23 PM Page 4

4 SYMPOSIUM HIGHLIGHTS

Endoscopy-Negative Reflux Disease: Acid-Related Disorder or Functional Disorder?

Endoscopy-Negative Reflux Disease 124). “The investigators looked at a very Endoscopy-Negative Reflux Disease likely causes of symptoms in many patients Is an Acid-related Disorder hard end point, a tough one to meet even Is a Functional Disorder with NEED. In a study of patients with Patients with nonerosive reflux disease for patients with obvious erosive esophagi- A significant minority of endoscopy- heartburn, ambulatory pH monitoring dis- (NERD) by endoscopy usually respond well tis: complete symptomatic relief,” said Dr. negative patients with reflux symptoms do tinguished a subgroup that had symptoms to proton pump inhibitors (PPIs) and hista- Richter.About half of the endoscopy-pos- not respond to acid-suppressing medica- but no evidence of acid reflux as well as a mine H2-receptor antagonists, leaving little itive patients, 48%, became symptom-free. tions.This and other evidence indicate that subgroup with evidence of intraesophageal doubt that NERD usually is an acid-related The endoscopy-negative group didn't fare such symptoms in the absence of esophagi- acid (Gut. 1995;37:7-12). All patients un- disorder, according to Joel E. Richter, MD, as well—29% were symptom-free by 4 tis represent a heterogeneous group of dis- derwent distal esophageal balloon disten- professor of medicine and chairman,depart- weeks, possibly because symptoms did not orders and are not simply a milder form of tion testing, a measure of visceral sensation. ment of gastroenterology and hepatology, consistently stem from acid reflux, according Those without evidence of reflux devel- Cleveland Clinic Foundation. acid-related causes. THE CONSULT to William D. Chey, oped pain at significantly lower levels of The literature defines NERD as the pres- Normal and abnor- MD, FACG, FACP, as- balloon inflation than did patients with ev- ence of typical gastroesophageal reflux dis- mal pH values are ¼ Esophageal endoscopy is per- sociate professor of idence of acid reflux. ease (GERD) symptoms due to intra- about equally likely formed on a 35-year-old male medicine and director In 66 endoscopy-negative persons with esophageal acid exposure in the absence of among symptomatic manual laborer with a 6-year his- of the GI physiology normal lower esophageal pH, who repre- visible esophageal injury at endoscopy (Am endoscopy-negative pa- tory of ongoing heartburn. laboratory at the Uni- sented 43% of a population of patients pre- J Gastroenterol. 2001;96:303-314).Thus, it is tients who undergo 24- versity of Michigan, senting with heartburn, as many as 97% had usually treated as an acid-related disorder, al- hour intraesophageal ¼ No mucosal abnormalities are Ann Arbor. either abnormal responses at balloon-dis- though NERD likely represents a continu- pH monitoring. When found. The term NERD tention testing and/or a positive Bernstein um of disorders ranging from true acid re- pH values are normal has entered common acid-perfusion test (Am J Gastroenterol. flux at one end to a functional problem at in such cases, the usage among gastroen- 1999;94:628-631). the other. chance that there is also coincident objec- terologists, but few patients to whom we Psychological disturbances, which are as- At many centers NERD accounts for up tively assessed acid reflux is greater than 50%. apply it are actually shown to fulfill the sociated with a variety of functional disor- to half of patients with GERD symptoms The normal-pH group with coincident term's definition, which attributes typical ders, are the likely cause of symptoms in a (Gastroenterology. 1987;92:118-124). “Re- symptoms and reflux, who therefore have a GERD symptoms to intraesophageal acid subset of patients with NEED. Such distur- cent data suggest that among such patients positive symptoms index, are said to have a exposure (Am J Gastroenterol. 2001;96:303- bances appear more prevalent in patients seen by general internists and family prac- sensitive esophagus.That is, they have a low 314). We rarely perform ambulatory with NEED than in those with esophagitis titioners, the rate of nonerosive GERD may pH threshold for acid-caused symptoms. esophageal pH monitoring in these pa- (Aliment Pharmacol Ther. 1997;11[Suppl even be closer to 80%,”said Dr. Richter. In another study, 12 of 18 endoscopy- tients, so we really do not know that acid 3]:57-62). And in a recent study, patients Conclusive data from at least three stud- negative patients with normal reflux levels is the cause of symptoms. Certainly, in pa- with psychiatric disorders were two to three ies show that GERD symp- were shown to have a posi- tients who respond to a PPI, times more likely than a tom severity is unrelated to tive symptoms index (Gut. acid is a likely cause of nonpsychiatric population whether endoscopy disclos- 1997;40:587-590). Those symptoms. Unfortunately, to suffer from heartburn (Al- es esophagitis (Eur J Gas- 12 patients showed signifi- 25%-50% of patients with iment Pharmacol Ther. troenterol Hepatol. 1998; cantly reduced symptom heartburn but no esophagi- 2001;15:1907-1912). There 10:119-124, Scand J Gas- severity and frequency and tis do not respond to a PPI. is also evidence to suggest troenterol. 1997;32:965-973). reduced antacid use with “What pathophysiologic that psychological stress may “There appears to be no improved quality of life. factors other than acid reflux alter esophageal sensation significant difference in the The six others, a minority, may be causing symptoms in and contribute to symptoms duration of symptoms, ei- showed no correlation be- this subgroup?” asked Dr. (Am J Gastroenterol. 1993; ther,” said Dr. Richter. tween symptoms and reflux Chey. “Nonacid reflux is a 88:11-19). Psychological Quality of life is similarly and therefore might have possibility,as are motility dis- factors have been shown to impaired in patients with had a functional disorder. orders, achalasia, abnormali- alter peripheral nerve mech- NERD and those with ero- JOEL E. RICHTER, MD Patients with NERD ties in visceral sensation or WILLIAM D. CHEY, MD anisms for pain signal trans- sive esophagitis (Am J Gas- have shown a significant brain-gut interactions, and mission and perception (Al- troenterol. 2001;96:S46-S53) and improves tendency to be male and older than 50 psychological disturbances such as somato- iment Pharmacol Ther. 1997;11[Suppl during symptomatic remissions (Scand J years of age, although hiatal hernia and obe- form disorders, depression, or anxiety.” 3]:57-62). Cognitive behavioral therapy, re- Gastroenterol. 1997;32:965-973). sity do not appear to be risk factors (Gas- Thus, patients with NERD might more laxation training,and other behavior-orient- Still, PPIs can prevent symptoms in most troenterology. 2001;120:A-434). Laparoscop- appropriately be said to have nonerosive ed treatments have been shown to improve cases. One study randomized 359 patients ic fundoplication appears less likely to esophageal disorders (NEED), which could heartburn and chest pain symptoms (Gas- with NERD to receive daily omeprazole resolve heartburn or produce patient-as- be defined as a heterogeneous group of dis- troenterology. 1995;108:619-620). Finally, 10 mg or 20 mg or placebo (Arch Intern sessed satisfactory results in NERD than in orders presenting as typical GERD symp- studies suggest tricyclic antidepressants and Med. 2000;160: 1810-1816). Among place- erosive esophagitis (Gastroenterology. 2000; toms in the absence of visible endoscopic selective serotonin reuptake inhibitors may bo recipients, 26% were heartburn-free af- 118:A-481). “Endoscopy-negative GERD esophageal injury. Published studies suggest alter esophageal sensation and improve ter 4 weeks; so were 51% of those who re- is not simply a milder form of reflux dis- that the demographics of NEED include symptoms in patients with noncardiac chest ceived omeprazole at the low dose ease,”said Dr. Richter.“Patients with it de- younger and female patients, nonobese per- pain (Gastroenterology. 1987;92:1027-1036, (P<0.001) and 77% of those who received serve effective therapy.”They should get a sons,and those without hiatal hernia—large- Dig Dis Sci. 1999;44:2373-2379, J Clin Gas- it at the high dose (P<0.001 as compared PPI initially,and if it doesn't work, nonacid ly the opposite of the demographics associ- troenterol. 1999;28: 228-232). with both other groups). causes should be investigated and treated. ated with erosive esophagitis. It is unlikely that any one therapy will A community-based study looked at Such patients may be more difficult to treat “This demographic is virtually identical work in all symptomatic, endoscopy-nega- symptomatic patients who were either pos- than those with erosive esophagitis, proba- to that which we see in functional disorders tive patients who do not respond to acid- itive or negative at endoscopy and were bly because NERD is a heterogeneous such as nonulcer dyspepsia or irritable bow- suppressing medications. Creativity and fur- given omeprazole 20 mg/day for 4 weeks group of different acid- and nonacid-relat- el syndrome,”said Dr. Chey. ther research are needed to develop a range (Eur J Gastroenterol Hepatol. 1998;10:119- ed disorders. ■ Nonacid-related pathophysiologies are of treatments for this group. ■

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