Medical therapy for gastroesophageal reflux disease

Medical Therapy for Gastroesophageal keflux Disease- DAVID A. JOHNSON,

M.D., Norfolk

virg,na

Gastroesophageal reflux disease (GERD) remains a ubiquitous problem, although therapeutic options continue to evolve. Effective therapy balls for understanding the pathogenesis. Key factors associated with GERD include incompetence of the lower esophageal sphincter, esophageal clearance, gastric contents, tissue resistance, and potency of the refluxate. Phase-type directed therapy remains the best treatment approach and histamine (H&receptor antagonists are now the cornerstone of therapy for patients not responsive to conservative measures. In a subset of patients with severe esophagitis who do not respond to conventional Hz-receptor antagonist therapy, efflcacy has been demonstrated with high-dose therapy. The acid suppressant omeprazole, highly effective in erosive esophagitis, is the drug of choice for esophagitis resistant to Hzreceptor antagonists. Despite effective forms of therapy, relapse rates are high in patients with severe GERD, and maintenance therapy typically is required. With near uniformity, efficacy end points for these agents have been directed toward relief of heartburn, regurgitation, and dyspepsia. Few data exist correlating relief of GERD and improvement of chest pain. Although therapeutic strategies for treating GERD have improved, empiric treatment of suspected GERD in the patient with noncardisc chest pain does not appear to be the optimal approach and should be reserved for cases where diagnostic testing is limited or unavailable.

From the Department of Internal Medicine, Gastroenterology Virginia School of Medicine, Norfolk, Virginia. tive and Liver

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astroesophageal reflux disease (GERD), a problem seen by physicians in all specialties, is best defined by including symptoms and/or evidence of tissue damage resulting from reflux of gastric contents. Symptoms of GERD may include chest pain. Histamine-2 (H&receptor antagonist therapy is a cornerstone for effective management of GERD symptoms. Treatment regimens have been modified by increasing standard closes of HZreceptor antagonists, aclministering combination therapies, and by administering more potent aciclsuppressive drugs, such as omeprazole. The conclition is frequently chronic, and long-term therapy may be problematic. This article will review various available treatment options for the short- ancl long-term management of patients with GERD, including a brief discussion of meclical therapy in patients with possible GERD-induced chest pain.

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PATHOGENESIS Gastroesophageal reflux clisease is not caused by a single abnormality; rather, it is a multifactorial process, wherein different abnormalities may preclominate in a given patient [l-5]. The factors that determine the clegree of reflus injury include structural integrity of the lower esophageal sphincter (LES), volume of the gastric reflusate, potency of gastric or gastrocluoclenal refluxate, efficiency of gastroesophageal clearance, and esophageal epithelial resistance and restorative repair capabilities. Anatomic Integrity

The integrity of the esophagogastric junction remains the primary cleterminant in gastroesophageal reflux. Several mechanisms of gastroesophageal acid reflux have been observecl during concomitant monitoring of the LES [l]. First, spontaneous reflux is associated with transient relaxation of the LES. This abrupt relaxation can follow, periocls of normal-to-high resting LES pressure and may also be evident during periods of low resting LES tone. This is the primary pattern of reflux episodes in normal subjects. Second, stress-inclucecl reflux happens when intra-abclominal pressure transiently overcomes the LES resting tone. This is likely the mechanism for reflux with straining, squatting, or stooping maneuvers. Finally, free gastroesophageal reflux is evident when resting LES tone is

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equal to or only a few millimeters of pressure above the intragastric pressure [2]. The somewhat confusing pathogenic relationship between a sliding hiatus hernia and esophagitis is now better defined. The consensus is that most patients with moderate-to-severe esophagitis have a hiatal hernia, although the converse that a majority of individuals with a sliding hiatal hernia do not have reflux disease is also well established [5]. Recent studies suggest that a hiatal hernia acts to impair refluxate clearance and may, thereby, augment mucosal contact time and sustained contactrelated injury [G]. Gastric Volume

Increased volume of gastric fluid also increases the rate of noncleglutitive LES relasations. Some authors report that delayed gastric emptying and its consequence, increased gastric volume, may be a major factor in GERD [7], although others clisagree [8,9]. More recent evidence suggests the presence of a hypersecretory state in some patients with GERD, particularly those unresponsive to standard closes of Hz-antagonist receptor therapy, such as patients with Barrett’s esophagus [lO,ll]. The initial report by Collen et nl [lo] showed that 10 of 12 patients who clid not respond to standard doses of raniticline had Barrett’s epithelium, compared with only one patient in the initial treatment response group. In a larger group of patients with Barrett’s esophagus, 36% had gastric acid hypersecretion [12]. Refluxate Potency

The effect of reflux-induced epithelial change depends in part on the potency of the refluxate. Hydrochloric acid alone may cause esophageal injury by protein clenaturization, but pepsin is the major constituent of the gastric pool responsible for esophageal injury [2]. Other components of the gastric refluxate that may contribute to esophageal injury include pancreatic enzymes and bile acicls [13171.

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amplitude in the distal esophagus ancl failed peristalsis may be continuing problems not improved with healing of the esophagitis [19,20]. Tissue Resistance

Epithelial injury is a consequence of contact with the refluxate. The capacity to withstand injury and repair ancl maintain tissue following injury is influenced by age and nutritional status, among other factors. When a hydrogen ion penetrates the preepithelial defense, several other epithelial defenses must be overcome before injury will occur [21,22]. The relationship of these processes to GERD is not well understood. MANAGEMENT AND TREATMENT Conservative Therapy

The primary goals of therapy for GERD are to eliminate symptoms ancl prevent complications. Conservative therapy appears to relieve reflux symptoms and is explored before embarking on more complicated and systemic therapies [23]. Dietary modification ancl weight loss, as well as headof-bed elevation with bed blocks or a bed wedge [24], may be effective. In patients with severe peptic esophagitis [251, sleeping with the head of the bed elevated complements pharmacologic therapy. Smoking cessation is perhaps not as critical as previously suggested [26]. The mechanism for smoking-inclucecl reflux appears to be largely due to increased spontaneous esophageal sphincter relaxations [27]. Alcohol climinishes the amplitude of the LES, peristaltic waves, and frequency of contraction [28,29]. Prolonged supine reflux does occur, particularly with nocturnal ingestion of alcohol followed by recumbency [30]. There has been a resurgence of interest in the role of alginic acicl in gastroesophageal reflux therapy. An alginic raft formecl on top of a gastric pool potentially is a very effective antireflux barrier [31331. Alginic acid-containing antacid preparations may well be considerecl the initial drug of choice in treating pregnant women with reflux symptoms c321.

Esophageal Clearance

Decreased esophageal clearance increases the duration of esophageal exposure to the noxious refluxate. Esophageal acid clearance occurs as a two-step process [2,18]: Esophageal peristaltic motor activity clears a volume of refluxate from the esophagus, and the residual acid then is neutralizecl by swallowed saliva. Normal peristalsis is extremely effective for volume clearance. However, esophageal peristaltic amplitude and frequency may be impaired in GERD [19]. In patients with severe relapsing esophagitis, decreased peristaltic

H2-Receptor Antagonists

Hz-Receptor antagonists are the “gold stanclarcl” for the medical therapy of gastroesophageal reflux, as has been demonstrated in many comparative trials, both with placebo and with alternative therapies [34-531. Cimetidine, ranitidine, nizatidine, and famotidine are currently approved as therapy for GERD. The level of acid suppression for later Hz-receptor antagonists such as famotidine, nizatidine, etintidine, and roxatidine is similar to that of ranitidine

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and cimetidine, although published studies are insufficient for a full evaluation [34]. Placebocontrolled studies with cimetidine [35-411, ranitidine [42-481, famotidine [49-511, and nizatidine [52,53] show essentially no statistically significant differences among agents in the treatment of GERD. Figure 1 illustrates schematically the similar efficacy among Ha-receptor antagonists. Pooled analysis of 51 controlled, double-blind trials clearly shows that Hz antagonists are superior to placebo, both in relieving typical GERD symptoms and in healing esophagitis [541. The efficacy of these agents is weighted by the duration of therapy (6,8, or 12 weeks) as well as the severity of mucosal involvement at the initiation of treatment [55]. Mean endoscopic healing rates from selected patient groups with mild esophagitis are 65-70% at 6 weeks, increasing to 80-90% after 12 weeks. Comparative healing rates for moderate esophagitis are 40-45% and 60-65%, respectively, and for severe reflux esophagitis, 20-30% and 3050%. Symptomatic improvement is much higher overall, even in severe reflux esophagitis, illustrating that symptomatic improvement does not parallel endoscopic improvement. Recently, higher doses of Ha-receptor antagonists have been used in some patients to promote healing, particularly of erosive esophagitis [56]. In one study, there was a clear advantage for ranitidine 300 mg q.i.d. over ranitidine 150 mg b.i.d. in patients with grades 2 and 3 esophagitis [57]. In the high-close group, complete endoscopic healing of esophagitis occurred in 75% of patients after 8 weeks of treatment compared with 54% of those

treatecl with the conventional regimen. The results for symptomatic relief were also significantly clifferent: 84% ancl 64%, respectively. A dose-ranging stcicly of patients with reflux esophagitis treated with famoticline founcl that the percent total reflux time with pH <4 was lower with famoticline 40 mg twice daily than with 20 mg twice daily or 40 mg at bedtime [58], inclicating that better results are achieved by greater suppression of acid secretion. High-close regimens are expensive, however, ancl 25-30% of patients clo not respond [55]. Prolonging high-dose therapy from 4 to 8 weeks increases healing and symptom relief to a limited extent (from 67% to 84%) [55]. Sucralfate

Sucralfate has a potential advantage in that it inhibits pepsin as well as absorbing bile salts, thereby inactivating them [59]. Furthermore, pretreatment with sucralfate decreasecl mucosal permeability ancl, consequently, esophagitis in rabbits [60,61]. Human stuclies have demonstrated that sucralfate may be superior to placebo in reflux esophagitis [62,63]. Other studies have shown efficacy comparable with that of antacicls [64] and Hareceptor antagonists [65-701, although one study has not [71]. Results of sucralfate trials are shown in Figure 2 [63,65,68-731. Prokinetic Agents

The use of prokinetic agents, which increase LES tone and stimulate gastric emptying, is appealing in that management is directed towarcl unclerlying factors that play a role in the pathogenesis of

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GERD. A profile of the trials to date using prokinetics is shown in Figure 3 [74-821. BETHANECHOL: Cholinergic agonists, in particular bethanechol, have been evaluated as a treatment for GERD. Bethanechol increases LES pressure and esophageal clearance, but it cloes not augment gastric emptying. Furthermore, bethanechol has a negative effect in that it stimulates gastric acid secretion and may decrease esophageal acid clearance. Results of efficacy studies in GERD have been conflicting [78,83,84]. Overall, bethanechol was not well toleratecl; side effects (abdominal

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cramps, diarrhea, urinary frequency, and blurred vision) limited acceptance of treatment. METOCLOPRAMIDE: Metoclopramicle is a procainamide derivative that increases LES pressure and amplitude of esophageal contractions, as well as accelerates gastric emptying in retention states [85,86]. Metoclopramicle not only stimulates the gastrointestinal smooth muscle but also coordinates gastric, pyloric, and duodenal motor activity, resulting in a net aboral movement. This clifferentiates the resultant action from the nonspecific cholinergic effects of bethanechol and explains the ob-

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Figure 2. Summary of trials of sucralfate in the treatment of gastroesophageal reflux disease. Numbers in brackets indicate source of data. Cim = cimetidine; fam = famotidine: ran = ranitidine; suer = sucralfate.

Figure 3. Summary of trials of prokinetic agents alone or compared with H,receptor antagonists in the treatment of gastroesophageal reflux dis ease. Numbers in brackets indicate source of data. Seth = bethanechol; cis = cisapride; dom = domperidone; meto = metoclopramide; other abbreviations as in Figure 2.

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served differences in efficacy between the two drugs [87]. Efficacy data in GERD are mised, with .some studies showing benefit [74,821 while another showed no difference from placebo [751. The major limiting factor of metoclopramicle is its i:elatively high side-effect profile [S51. DOMPER~DONE: Dompericlone is a peripheral clopamine antagonist that, in contrast to metoclopramide, has no central nervous system effects, thereby improving its side-effect profile consiclerably. Dompericlone’s prokinetic and gastric effects and its ability to augment gastric emptying have beeli i&l1 documented [75,58], although overall results in GERD have been negative in wellcdntrollecl studies [79,89-921. Studies suggest that the primary effect of clompericlone in patients with reflux esophagitis may be to improve gastric emptying rathbr than esophageal motility. Accordingly, it does not have a role in the primary management of most patients with GERD 1931. CISAPRIDE: Cisapricle has no anticlopaminergic action. It improves propulsive activity of the esophagus, stomach, and small and large bowel and augments esophageal peristalsis, LES tone, and gastric emptying [94]. Cisapride increases LES pressure and decreases reflus [95-991. Cisapricle therapy compares favorably with metoclopramicle [7G] and HZ-antagonists [77,501. Overall, cisapricle appears to be effective in the treatment of reflus clisease, although its efficacy appears greatest in mild disease [loo, 1011. ERYTHROMYCIN: Erythromycin, a potent prokinetic agent, mimics the effect of the gastrointestinal polypepticle motilin on gastrointestinal motility. Controlled trials of acute therapy with a 4-week follow-up have demonstrated benefit in gastric emptying with corresponding symptomatic improvement [ 1021. One preliminary report that evaluated its potential use in GERD found that erythromycin did not significantly improve acid exposure time ancl heartburn episodes, although there was a strong tendency for clecreasecl cluration of reflux episodes [103]. Further stuclies are neeclecl to ascertain its effectiveness and appropriate close, as well as its potential long-term use in reflux patients. Omeprazole

Omeprazole, a substituted benzimidazole, inhibits the gastric parietal cell proton pump, blocking the final common step in luminal acid secretion [1041, and is approved for short-term use in gracle 2 or greater esophagitis. Placebo-controlled trials [105,106] and trials comparing omeprazole with either cimeticline [107] or raniticline [108-1121 show an advantage for omeprazole in symptom relief and endoscopic healing. None of the omeprazole trials 5A-92s

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have used relief of GERD-induced chest pain as a symptom goal. In controlled randomized trials, esophagitis was healed in 57-74% of patients after 4 weeks of omeprazole therapy and in 78-97% after 8 weeks; comparable rates in patients treated with H,-receptor antagonists are 27-43% and 28-5G%, respectively (Figure 1). Meta-analysis demonstrates a 3540% therapeutic advantage in favor of omeprazole after both 4 ancl8 weeks of therapy [1131. In studies that stratified patients according to grades of esophagitis, omeptiazole has a greater advantage in patients with more severe disease [1131. Omeprazole is effective for the treatment of patients with resistant esophagitis, even after longterm, high-close HZ-receptor-antagonist treatment [ 112,114-1231. Healing of refractory ulcers, particularly in Barrett’s esophagus, appears possible with omeprazole [122], which may reflect the higher prevalence of acid hypersecretion in patients with Barrett’s esophagus [12]. Reports from European trials indicate that 10% of patients with severe esophagitis treated with omeprazole will not heal, even with high closes [123,1241; therefore, other pathophysiologic factors, in addition to acicl reflux, are important in esophagitis [ 1251. The concomitant use of medication that is potentially caustic to the esophagus, such as nonsteroiclal anti-inflammatory clrugs (NSAIDs), may be of particular concern. However, the trials reporting omeprazole resistance did not evaluate this. The main safety issue with omeprazole has been its ability to produce hypergastrinemia and gastric carcinoicl tumors in rats and the consequent implications for humans. Data suggest that short-term omeprazole therapy is safe, although it produces slight hypergastrinemia [ 113,126,127]. Combination Treatment

If standard single-drug therapies are not effective, combination therapy with an acid-suppressive agent and a motility agent may be more effective. This approach seems logical in patients with clocumentecl abnormal gastroesophageal motor function. Trials supporting this premise inclucle evaluations of the use of He-receptor antagonists combined with metoclopramicle [128], clompericlone [129], or cisapride [1301. Carbenoxolone/antacicl am1 an alginate preparation were more effective in patients failing routine management with antacids [131]; cimetidine and an alginate/antacid were more effective than either preparation alone [132]; and sucralfate combined with cimetidine is more effective than cimeticline alone [73]. A profile of the combination therapy trials to date is shown in Figure 4 [73,90,128-1321.

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MAINTENANCE THERAPY Reflux disease is generally a chronic condition. Patients with reflux esophagitis tend to relapse after discontinuing treatment, regardless of the therapeutic agent usecl [105,133-1381. There are few data regarding maintenance therapy. In a l-year study of patients with GERD in symptomatic remission, the cumulative protective effect of cimetidine with a twice-daily regimen (70%) was numerically greater than a bedtime (54%) or placebo (60%) regimen [136]. Maintenance therapy with ranitidine twice daily is effective, but there is no difference between placebo and bedtime dosing of ranitidine [ 1381. Studies of continued treatment with cimetidine plus metoclopramide [135] or cisapricle alone [ 139,140] suggest efficacy in preventing relapse. Data on maintenance treatment with omeprazole are emerging [117,141,142]. While the use of omeprazole emphasizes the importance of longterm potent acid inhibition for treating complex resistant esophagitis, careful surveillance of its safety profile remains obligatory [113]. Concern over the proliferative effects of hypergastrinemia remains. Recent data suggest that the volume of argyrophilic cells in the oxyntic mucosa increases with chronic omeprazole therapy; however, no clysplasia of gastric and argyrophilic cells was seen during maintenance therapy for l-5 years [142]. A profile of the trials evaluating maintenance therapy in GERD is shown in Figure 5 [115,117119,133,139,141]. Overall, it appears that patients with chronic gastroesophageal reflux will require continuous

Figure 4. Summary of trials of combination therapy in the treatment of gastroesophageal reflux disease. Vertical axis represents percentage of patients with symptomatic relief at 6-8 weeks of therapy. Numbers in brackets indicate source of data. Alg = alginate; carb = carbenoxolone; other abbreviations as in Figures 2 and 3.

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therapy. It seems most reasonable to achieve early symptomatic relief with either high-dose Ha-antagonist therapy or omeprazole, followed by twicedaily maintenance therapy with Hz blockers. Periodically, patients may need a more potent acidsuppressive regimen. Combination therapy with prokinetic agents may be advantageous in selected patients. There is some concern, however, that severe relapsing esophagitis results in a residual esophageal peristaltic dysfunction in patients [143,144]. Conceivably, allowing patients to relapse repeatedly may lead to progressive dysfunction of the esophageal acid clearance mechanism, which may further aggravate the problem. For this reason, evaluation for antireflux surgery should be considered in selected patients.

MEDICAL THERAPY FOR GERD-INDUCED CHEST PAIN Data from patients with GERD-induced chest pain are limited either with regard to overall resolution of symptoms or time to symptom relief. One recent study suggests that relief of heartburn or endoscopic healing of esophagitis can be used to predict relief of GERD-induced chest pain [65]. Overall symptomatic relief of heartburn, regurgitation, and chest pain in response to ranitidine was 40%, 72%, and 33%, respectively, and endoscopic healing occurred in 31%. However, the authors did not indicate if symptomatic improvement ‘correlated predictably in each patient. In patients with GERD-related chest pain who were treated with sucralfate, complete symptomatic relief of heartburn, acid regurgitation, ancl chest pain was re-

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SYMPOSIUMON UNEXPLAINEDCHESTPAINI JOHNSON TABLE I Advantages and Disadvantages of Empiric Therapy in Patients with Noncardiac Chest Pain Advantages Cost (inftial)

Limited availability of testing “Simple” therapy Sideeffects of testing

Disadvantages

’

Delayto diagnosis Recurrent evaluations Placeboeffect Drug costs Specialist’srole: need for rapid diagnosis Difficultfor patient to adhere to dietary/mechanical measureswithout a diagnosis Sideeffects of therapy

ported in 34%, 6’7%, and 67%, respectively, and endoscopic healing occurred in 47% [65]. Data on the intrapatient correlation of symptom relief and healing were not supplied. Hence, it appears that endoscopic healing may not be required for relief of chest pain. If therapy for GERD is available and if GERD is the most common treatable gastrointestinal cause of unexplained chest pain, is-there a role for empiric therapy in patients with unexplained chest pain? The advantages and disadvantages of empiric therapy are listed in Table I. The potential savings in cost for drugs over procedural testing may not be recognized if high-dose Ha-antagonist or

omeprazole therapy is required over several weeks to achieve symptom relief. Furthermore, with a high placebo response rate, predictably 25-30% with Hz antagonists but lower with omeprazole, it may be unclear whether the initial response was due to effective treatment of the pathologic process. Thus, how does one treat symptom relapse after a course of empiric therapy? In addition, consultants may be justified in performing direct testing initially, particularly those in tertiary referral centers who may have only a short evaluation period because patients live far away. Overall, it is clear that we have more questions than answers with respect to the treatment of GERD and symptomatic improvement of chest pain. Because of the previously cited shortcomings of the reflux trials conducted to date, physicians are at a disadvantage for predicting symptom response to medical therapy-both initial and long-term treatment. Conceivably, the current initial approach of diagnostic testing may be modified to favor high-dose empiric therapy. Controlled trials to answer these questions are under way. For the present, it seems most reasonable to define the disease by directed testing. Selection of appropriate medical therapy is guided by current data on relief of the more typical symptoms of GERD and healing of esophagitis. Resolution of the issues related to

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GERD therapy and chest-pain response await collection of scientific data from controlled trials. “‘I have no data yet. It theorize before one has begins to twist facts to theories to suit -facts.” Sherlock Holmes in “A

is a capital mistake to the data. Inselasibly, one suit theories, instead of Scandal in Bohemia”

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