Raising the Bar in GERD Care for Seniors

National surveys indicate that approximately half of the adult population of the United States experiences heartburn sometime during each year, and that at least 20% report symptoms of heartburn and regurgitation at least weekly. It occurs most frequently at night or during the daytime after eating or while exerting upward pressure on the lower esophageal sphincter (LES) by such common activities as bending. Eight percent of American adults report having heartburn and acid regurgitation at least twice per week, and approximately 20% have taken non-prescription histamine type-2 receptor antagonists (H₂RAs) at some time during the last few years.

Although heartburn is generally a result of gastroesophageal reflux (GER), it is not all clinically similar, an observation that introduces a confusion of nomenclature. When drugs for combating heartburn were initially subjected to clinical trials, recruitment was restricted to individuals with endoscopically proven erosive esophagitis, because FDA approval hinged on a drug’s effectiveness in curing an observable disease entity. More recently, however, it has become clear that heartburn and regurgitation may occur frequently without erosive esophagitis, and that gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD) are not reliably distinguished on the basis of symptom severity. Individuals with both disorders, if untreated, have a health-related quality of life comparable to that of people with untreated duodenal ulcers and inferior to those with angina pectoris because both NERD and erosive GERD are chronic pain syndromes that require continuous care. The treatment goals are symptom relief and halting progression to Barrett’s esophagus.

This symposium was supported by an unrestricted educational grant from Eisai, Inc. and Janssen Pharmaceutica, Inc.

Compelling Issues in GERD Management in Older Adults

Because both GERD and NERD are chronic disorders in which the severity of symptoms may be age-related, the aging of the American population is a significant factor influencing their prevalence. Martin J. Gorbien, MD, FACP (Rush-Presbyterian-St. Luke’s Medical Center) observed that more than 13% of the population is now over the age of 65 years, and that the group of people over the age of 80 years is the fastest growing segment of the population in the United States. Thirty percent of the population is now projected to survive until age 80 or above, and between ages 75 and 79 the mortality rate is only 6%. Within this elder population, individuals free of even occasional gastroesophageal reflux are rare. By the age of 65 years, the prevalence of reflux rises to 59% and continues to rise thereafter.

The issue, of course, is not age per se but changes in functional status associated with aging. It is well established, for example, that renal function declines in a linear fashion with age, a factor that must be taken into consideration when prescribing drugs that are excreted by the kidney. With regard to gastroesophageal reflux, aging affects all of the esophageal cytoprotective mechanisms of normal physiology resulting in (i) decreased salivary secretions that bathe the esophagus, (ii) diminished esophageal mucosal resistance, (iii) decreased esophageal motility and clearance, (iv) decreased LES tone and/or transient relaxation of the LES and (v) delayed gastric emptying, thus extending the period of time after eating when upward pressure may be exerted on the lower esophageal sphincter. Although none of these changes may be important individually, together they increase the amount of the esophageal mucosa that may be exposed to gastric acid, and pepsin.

In addition, although the elderly comprise 13% of the population, they receive over 30% of all prescriptions. Two-thirds of individuals over age 65 use more than one medication daily and the average number ranges from 5 to 12 drugs daily in various series studied. When two drugs are prescribed, the potential for an adverse interaction is 6%, but the potential increases to 50% with five drugs and to virtually 100% with eight drugs or more. Many of these interactions have gastrointestinal effects that may contribute to reflux, some of them by modifying the integrity of the LES. Drugs that promote reflux include aspirin, non-steroidal anti-inflammatory drugs, theophylline, nitrates, calcium channel blockers, anticholinergics and prostaglandins. Managing the aggregate anticholinergic load is especially important in this population. Bed-bound patients taking bisphosphonate for osteoporosis are especially susceptible to gastroesophageal reflux because of the risks of taking it without strict compliance with postural instructions.

Certain medical conditions also contribute to reflux disease including Parkinson’s disease, stroke and diabetes. Hiatal hernia may also be a contributing factor because it deprives the esophagus of its “second sphincter.” A lifestyle dominated by immobility may also be a contributing factor.

The typical presentation of reflux consists of heartburn and regurgitation, though heartburn is frequently not the primary symptom in older individuals. Atypical presentations include non-cardiac chest pain, epigastric pain and dyspepsia, nausea, vomiting and belching. Some patients, especially whose with late-state dementia, may have swallowing disorders. Anorexia, anemia, fatigue and weight loss are common. Chronic exposure to acidic content may also result in persistent hiccups, sore throat, hoarseness or chronic cough. Patients may also have recurrent pneumonia from aspiration of gastric acidity or wheezing from adult-onset asthma associated with chronic acid exposure. Dental enamel erosion is seen occasionally. Bleeding, anemia, dysphasia and weight loss are considered alarm symptoms.

The potential complications of reflux disease are principally ulcer, stricture, Barrett’s esophagus and adenocarcinoma of the esophagus. Barrett’s esophagus consists of tongues of columnar metaplastic epithelium in the esophagus that may progress to dysplasia and then to neoplasia. Thus, it is thought to be a precursor lesion for adenocarcinoma, the principal cause of mortality associated with reflux disease though it is a very uncommon outcome. Gastro-intestinal bleeding, recurrent pneumonia from aspiration of acidic content, adult-onset asthma, sleep disorders and malnutrition also occur.

Raising the Bar in Reflux Disease Care by Understanding PPI Pharmacology

John R. Horn, PharmD, FCCP (University of Washington) noted that although all the proton pump inhibitors (PPIs) currently available in the United States are effective and well tolerated, they have different pharmacology that can influence drug selection for particular patients. All of these agents, which are all weakly alkaline, are prodrugs that require conversion to an active species. This conversion occurs by protonation upon exposure to the acidic environment within the secretory canalicular space of the parietal cell. Following conversion, the active species binds to the proton pump.

Although all PPIs go through this process, each has a different PKa, that is, a different point in the parietal cell’s acidic range at which 50% of the drug’s molecules are protonated. Among the FDA-approved PPIs (rabeprazole, lansoprazole, omeprazole, pantoprazole and esomeprozole — the S-enantiomer of racemic omeprazole), the PKa range is from 5.0 for rabeprazole down to 3.8 for pantoprazole. At a pH of 1.2, which is typical of the parietal cell while an individual is eating, all of these drugs are activated within 1.5 to 5 minutes. However, when eating ceases and the parietal cell stops secreting, the environmental pH begins to rise; and as it passes through the individual drug’s PKa, the drug’s activation slows down and eventually stops. At a pH of 5.1, rabeprazole activates in an average of 7.2 minutes compared with 84 minutes for omeprazole, 90 minutes for lansoprazole and almost 5 hours for pantoprazole.PPIs have an average plasma half-life of approximately 60 minutes, yet they have a very long duration of action. This apparent contradiction is explained by the irreversible manner in which the active species binds to the proton pump. Any molecules that fail to bind are eliminated quickly, so the broader the pH range over which binding occurs, the more nearly saturated the proton pumps become. Thus, the PKa may in part determine both the onset and the duration of activity for suppressing acid secretion.

Another area in which PPIs differ is their metabolism. They are all metabolized by the CYP2C19 and CYP3A4 pathways, but in different proportions. The 2C19 isozyme is predominant in the metabolism of omeprazole, esomeprozole and pantoprazole, and the two pathways contribute approximately equally to the metabolism of lansoprazole. In the case of rabeprazole, however, 2C19 and 3A4 are secondary pathways, as the drug is metabolized primarily by non-cytochrome-mediated processes.

These are important differences for two reasons. First, omeprazole and esomeprozole inhibit 2C19 and are, therefore, dose-related inhibitors of their own metabolism. Doubling the dose of either of these agents induces a five- to six-fold increase in plasma concentration. Second, 2C19 is genotypically distributed. Pharmacogenetic studies have demonstrated that about 97% of Caucasians have one or two functional genes for this enzyme. The remaining 3% lack the genes to produce the 2C19 enzyme and are considered to be poor metabolizers of drugs that relay on 2C19. In the Asian population, however, 15% to 25% of individuals are poor metabolizers of CYP2C19. In a crossover study of the affect of genotype on the pharmacokinetics of PPIs using omeprazole, lansoprazole and rabeprazole, subjects were aggregated as homozygotic or heterozygotic and as extensive metabolizers of 2C19 or as poor metabolizers. While there was approximately a six-fold difference in plasma concentrations between rapid and poor metabolizers when taking omeprazole and a lesser increase when taking lansoprazole, there was no significant difference between the two genotypes when taking rabeprazole (Sakai et al. Pharm Res 2001;18:721).

Other studies indicate that the pharmacodynamic effects of PPIs mirror the pharmacokinetic differences. Importantly, these differences translate directly into clinical outcomes. A recently published study, the first that evaluated the affect of genotypes on erosive esophagitis cure rates, utilized lansoprazole in patients with erosive GERD. Homozygous extensive metabolizers had a cure rate of approximately 45%, whereas the cure rates for heterozygous and poor metabolizers were 70% and 85%, respectively (Furuta T et al. Clin Pharmacol Ther 2002;72:453).

The overall healing rates of erosive esophagitis for all PPIs are in the range of 80% and 90%. All of the PPIs are dosed near the top of the dose-response curve, and extra drug concentration such as that achieved by giving higher doses of esomeprozole yields a small increase in patient response. In a study comparing rabeprazole 20 mg daily and esomeprozole 20 mg daily on days 1 and five of treatment, the rabeprazole response exceeded that of esomeprozole on both days, though by a smaller margin on day 5 as the activity of esomeprozole increased over time (Warrington T et al. Aliment Pharmacol Ther 2002;16:1301).

There are few drug-drug interactions with PPIs, but Dr. Horn cautioned that these agents may affect drugs for which absorption is dependent on gastric acidity. As the intragastric pH increases, the absorption of anti-fungal drugs and anti-viral agents, for example, may decrease. Since PPIs can bind only to active proton pumps, they should be taken 30 to 60 minutes prior to meals.

Not all GERD Patients are Equal: Clinical Strategies in GERD Therapy

Neil H. Stollman, MD (University of California San Francisco) observed that in several trials consisting of as many as 400 patients with symptoms of reflux disease confirmed by 24-hour esophageal pH probe, between 50% and 70% of patients are negative for erosive esophagitis at endoscopy. He hypothesized that these patients may have hypersensitivity of the esophagus and heightened permeability of the esophageal epithelium resulting in nociceptive stimuli. They may also have enhanced chemoreceptor sensitivity. Despite the absence of esophageal erosion, however, symptoms may be as severe in these NERD patients as in GERD patients, with the result that symptom severity is not a reliable diagnostic hallmark. The diminished quality of life for GERD and NERD patients is also indistinguishable in mild, moderate and severe cases.

Nevertheless, symptoms are very useful for recognizing reflux disease in general. A 24-hour measurement of esophageal acidity by probe is 90% positive for predicting reflux disease in individuals who present with heartburn and regurgitation, who describe their symptoms as nocturnal, postprandial or associated with bending, and who get temporary relief from non-prescription antacids.

Thorough diagnostic testing is generally not required for the diagnosis of reflux disease except in patients who fail an empirical course of PPI therapy. Typical heartburn should generally be eliminated by such a course within 2 weeks in most patients, although atypical symptoms such as chronic cough and hoarseness may take up to 4 months. For patients who fail empiric therapy and do not have alarm symptoms such as dysphagia and bleeding, 24-hour pH monitoring while the patient is off medication is “the best test to define or exclude this disease,” Dr. Stollman said. Alarm symptoms should prompt a more thorough workup, and chest pain should be investigated by standard cardiology evaluation. Barium radiography has no role in the diagnosis of reflux disease, as many true GERD patients have normal endoscopies. It may be useful, however, in patients with dysphagia who may have reflux-related ulcers or strictures or esophageal cancer.

“The more difficult and probably the most important clinical question is who gets endoscopy in reflux disease,” Dr. Stollman said. The main reason for endoscopy in this setting is to rule out Barrett’s esophagus, but whom to screen for Barrett’s esophagus is a matter of judgment. In general, endoscopy is not sufficiently sensitive to diagnosis GERD or NERD. Moreover, while on the one hand one does not want to subject patients unnecessarily to an expensive and potentially morbid procedure, on the other hand, missing a pre-cancer or cancer is unacceptable. One of the most reliable guides to resolving this issue is the chronicity of symptoms: the longer the patient has had heartburn, the greater the probability of Barrett’s esophagus. In addition, Barrett’s esophagus and esophageal adenocarcinoma are almost predominantly diseases of Caucasian males. Thus, one should be more inclined to take white males with long-standing reflux symptoms to endoscopy, and less likely to do so with females or males of other races. The exception is the reflux patient with alarm symptoms, scleroderma or a family history of upper gastrointestinal malignancy, who should be endoscoped regardless of gender and race.

The treatment of reflux disease involves lifestyle changes plus pharmacologic intervention. Lifestyle changes include elevating the head of the bed, eliminating all eating and drinking for three hours prior to recumbency, and avoiding caffeine, alcohol and tobacco smoke intake.

With regard to pharmacologic intervention, long-term maintenance in this chronic disease is probably more important than acute therapy. Nevertheless, one of the most rigorous endpoints for evaluating the benefit of PPIs is the number of days of therapy required to reach the first day of complete 24-hour symptom relief. In one placebo-controlled trial using this endpoint in patients with erosive esophagitis, total resolution of heartburn was achieved in a median of 2.5 days with rabeprazole 10 mg and in a median 3.5 days with rabeprazole 20 mg compared with 19.5 days with placebo. The results in both treatment arms were statistically significant with respect to placebo (Kahrilas PJ et al. Gastroenterol 2002;122(4):A1280). In the same trial, approximately 20% of the population was cured of heartburn by rabeprazole within 2 weeks and an additional 31% by the end of week 4, and nocturnal heartburn was resolved in 1.5 days compared with 7.5 days with placebo. Another rabeprazole trial, which is summarized in Figure 1, evaluated complete relief of multiple systems. Figure 2 summarizes the findings of several trials as an approximate comparison of complete symptom relief at the end of 4 weeks from rabeprazole 10 mg and from two dosages of esomeprozole, adjusted for placebo effect.

Because of the importance of long-term therapy, however, patient status at the end of week 4 may not be a compelling statement of PPI efficacy. In an early effort to assess long-term efficacy, Australian investigators conducted an evaluation of relapse rates in 107 patients who had documented healing of erosive esophagitis with omeprazole (Hetzel DJ et al. Gastroenterol 1988;95(4):903). On long-term follow-up, 82% of subjects had relapsed within 180 days of treatment cessation, highlighting the need for maintenance therapy in the large majority of patients. In a placebo-controlled trial utilizing maintenance with rabeprazole 20 mg, the remission rate at week 52 in patients with erosive gastritis was 86% (Birbara C et al. Gastroenterol Hepatol 2000;12(8):889).

There is an appropriate role for laparoscopic fundoplication in a subset of GERD patients, but a recent 10-year follow-up study indicates that nearly two-thirds of patients still required anti-reflux medication and almost one-third remained on PPI therapy (Spechler SJ et al. JAMA 285(18):2331). Thus Dr. Stollman advised that no patient be offered surgery in the expectation of definitively avoiding long-term medical therapy.

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