Brought to you through an educational grant from TAP Inc.Behavioral Objectives
After completing this continuing education article, the pharmacist should be able to:
Gastroesophageal reflux disease (GERD) is defined as the symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus.1 Left untreated, GERD can be associated with unpleasant symptoms as well as a number of complications.
The epidemiology and presentation of GERD in elderly populations is somewhat different than in younger patients. Likewise, elderly patients have unique characteristics that influence management. The purpose of this article is to discuss the symptomatology, pathophysiology, presentation, diagnosis, and management of GERD as they apply to elderly patients.
The overall prevalence of GERD has been estimated at 10% to 20% in the Western world, and nearly 20 million Americans suffer from the disease.2 The prevalence of GERD appears to be similar in young and elderly patients. Although the prevalence of GERD is not higher in the elderly, the frequency of complications such as esophagitis, stricture, and Barrett's esophagitis is higher in older patients.3 In the Western world, the incidence is approximately 5 per 1000 person-years.4
The effect of increasing age on the incidence of GERD is unclear, with some studies showing an association with increasing age,5,6 others suggesting no association,7 and still others suggesting an increasing incidence up to a certain age (55-70 years) and then a decline.8,9 Taken together, the data suggest that the incidence of GERD symptoms does not increase with aging. As the population ages, however, the number of elderly patients with GERD will, of necessity, increase.
The impact of untreated GERD on health-related quality of life (QOL) is marked and often underappreciated. GERD substantially impacts patients in a number of ways, including symptoms, complications, and inconvenience of treatment. QOL may be affected by disrupted sleep, reduced concentration at work, and interference with daily activities such as exercise, housework, or gardening. Some authors have suggested that the impact on QOL is similar in magnitude to that of such disorders as angina pectoris or congestive heart failure.2
Although GERD itself is seldom life-threatening, prolonged or severe disease may lead to complications. As one might expect, these complications carry with them significant impairment of QOL. Elderly patients tend to present with complicated disease more frequently and therefore may be disproportionately affected, relative to younger patients.
The economic burden of GERD also is substantial, with nearly $10 billion in direct costs alone. It is 1 of the 5 most costly gastrointestinal disorders.2 In 2004, GERD was responsible for more than 5.5 million outpatient clinic appointments, while dyspepsia and gastritis accounted for an additional 2.2 million visits.10 In 2004, more than 8 million prescriptions were filled for proton pump inhibitors (PPIs) alone, and the total cost of PPIs in 2004 was >$10 billion, including OTC preparations.10
GERD also has been shown to be responsible for decreases in work productivity. These losses appear to be directly related to the severity of symptoms as well as to the presence of nocturnal symptoms.2 Data from Japan suggest that work productivity is further diminished by the need for physician office visits related to GERD.11 These data imply that control of symptoms and prevention of complications are cost-effective approaches to the management of GERD.
A number of risk factors have been suggested for GERD, some of which may be more common in elderly populations. Data from a United Kingdom twin registry demonstrate a significant association with a parental history of reflux disease, as well as a higher concordance between monozygotic twins than between dizygotic twins.5 A second study of citizens of Olmsted County, Minn, demonstrated an association of GERD with a history of reflux disease in an immediate relative, but not with a history of reflux in the family of the spouse.7 These data suggest a genetic component to the development of GERD.
Although a clear association exists between pregnancy and GERD, no study has demonstrated gender as an independent risk factor.4 Other identified risk factors include increased body mass index,5,8,9 the use of certain medications (eg, anticholinergic agents, nitrates, oral steroids),5,8 and smoking.6,7 No clear demonstration has been made between coffee or food intake and symptoms of GERD.12
Whereas age has not been shown to be an independent risk factor, older patients may be more likely to possess other risk factors. For instance, elderly people are known to take more medications than younger people, and many of the agents that they take, such as nitrates, are associated with GERD. Likewise, elderly patients are more likely to have hiatal hernias and diseases associated with GERD, such as neurologic and respiratory diseases.
The pathogenesis of GERD is multifactorial. The following are contributions:
Over time, reflux of gastric contents results in esophageal damage. The reflux barrier may be impaired by alterations in LES tone (including alterations caused by drugs) or the presence of a hiatal hernia.13 Although LES dysfunction never has been shown to increase with age, elderly patients more frequently take drugs that can alter LES tone and are more likely to have hiatal hernias.14
Elderly patients may have decreased resistance to acid exposure because of decreased saliva production and decreased esophageal motility.15-17 Perhaps the most important risk factor for the development of severe reflux complications in the elderly is the cumulative injury to esophageal mucosa due to poorly controlled disease.3
A number of commonly used drugs may contribute to GERD (Table 1). These drugs may act by impairing LES tone or by directly injuring the esophageal mucosa.18 Often, the use of these medications is more common in elderly patients. A crucial component of the evaluation of any patient with suspected GERD is a review of the medication profile for potentially offending agents.
Additionally, some neurologic diseases may affect esophageal and gastrointestinal motility and/or tone and contribute to the development of GERD. Many of these diseases?such as diabetes, Parkinson's disease, stroke, and dementia?are more common among older patients. These factors must be taken into account in the evaluation of elderly patients with symptoms suggestive of GERD.
A 73-year-old woman with a medical history of hypertension, atrial fibrillation for which she is anticoagulated with warfarin, and mild renal insufficiency presents to her physician complaining of mild symptoms consistent with GERD. The physician chooses to initiate pharmacologic therapy and asks for your assistance. Which of the following is most accurate?
Answer is at the end of the article.
The classic symptoms of GERD include heartburn, regurgitation, or both, which commonly occur after meals and especially after large or fatty meals. These symptoms often are aggravated by recumbency or bending forward and are relieved by antacids.1
Interestingly, there are significant differences in the presentation of GERD in elderly patients, compared with that in younger people. Elderly patients are less likely to present with the classic symptoms and are more likely to present with dysphagia, vomiting, chest pain, and pulmonary difficulties.3,19
The absence of traditional symptoms may be related to decreased acidity of the gastric contents or decreased esophageal sensitivity with age. The symptoms that are more frequent in the elderly reflect the increased likelihood of presenting with erosive esophagitis or complicated GERD.3
The absence of traditional symptoms means that clinicians must be particularly vigilant in the detection and management of GERD in elderly patients. Extraesophageal complaints?such as chest pain that has been determined to be noncardiac, prolonged laryngitis, chronic cough, or hoarseness?are common in the elderly, and GERD must remain in the differential diagnosis when such complaints are present.
Several strategies are available for the diagnosis of GERD. They include diagnosis based on symptoms, endoscopy, and esophageal pH monitoring (the gold standard).
Esophageal monitoring is performed by passing a pH probe into the esophagus to just above the gastroesophageal junction. The probe is used to collect data regarding the pH of the lower esophagus, and thus to evaluate for the reflux of acidic gastric contents over the course of a 24-hour period.
Current guidelines suggest that it is reasonable to offer empiric therapy to patients who present with classic symptoms. It also is reasonable to assume a diagnosis of GERD in patients who respond to appropriate therapy.1
More invasive modalities, such as endoscopy, should be pursued in patients who do not respond to therapy; when there are symptoms suggestive of complicated disease (eg, dysphagia, odynophagia, bleeding, weight loss, or anemia); and when the duration of symptoms is sufficient to place the patient at risk for Barrett's esophagus (generally >5-10 years).1 Some authors have suggested that endoscopy be used early in the evaluation of all elderly patients due to the higher frequency of complicated disease concomitant with less severe symptoms.3 Consequently, any elderly patient suspected to have GERD should undergo physician evaluation so that the appropriate diagnosis may be made.
The treatment of GERD in the elderly follows the same general principles as for younger patients. Because elderly patients are more likely to have erosive esophagitis or complicated disease, however, they often require more aggressive medical therapy.3
The first step in the treatment of GERD is lifestyle modifications, including alterations of dietary habits and mechanical methods to decrease the reflux of gastric contents (Table 2). Although these changes have been shown to decrease the exposure of the lower esophagus to acid, the true efficacy of these maneuvers never has been rigorously demonstrated. Furthermore, lifestyle modifications alone are unlikely to control symptoms in the majority of patients.1
A number of pharmacologic options are available for the treatment of GERD. Conceptually, these agents target the dysmotility component of GERD (ie, promotility agents) or, more commonly, they decrease the acid production in the stomach to decrease the caustic consequences of refluxed contents (ie, acid-suppressing or neutralizing agents). These agents include OTC antacids and antireflux agents (eg, alginic acid), promotility agents (eg, metoclopramide and cisapride), histamine receptor type 2 (H2) antagonists, and PPIs.
Antacids and alginic acid have been shown to be more effective than placebo for the relief of symptoms triggered by meals.20,21 The results of 2 long-term trials suggest that effective symptom relief can be achieved in ~20% of patients22,23 and may be appropriate for the management of mild or intermittent symptoms. These agents must be used with caution in the elderly, however, due to toxicity and side effects, including salt overload, constipation, diarrhea, hypercalcemia, and interference with the absorption of other drugs, particularly antibiotics.1
Two prokinetic agents, metoclopramide and cisapride, currently are available for the management of GERD. Conceptually, these agents are attractive, because poor esophagogastric motility?including LES dysfunction and delayed esophageal and gastric clearance?is a central component of GERD pathophysiology. These agents are effective, alone or in combination with H2 antagonists, in the treatment of nonerosive reflux disease or mild esophagitis, particularly when there are associated symptoms of nausea, bloating, and vomiting.3 These agents also are useful in the management of diabetic patients who frequently suffer from gastroparesis.
Because of its antidopaminergic activity, however, metoclopramide is associated with side effects in up to one third of elderly patients. These side effects include muscle tremors, spasm, agitation, insomnia, drowsiness, confusion, and even tardive dyskinesia.24 Although cisapride has fewer central nervous system side effects, it has been withdrawn from general availability in the United States due to QTc prolongation and the associated increased risk of ventricular arrhythmias. Cisapride is available only via a limited-access program to patients meeting strict criteria.
Acid-suppressing agents target the production of acid by parietal cells in the stomach. Physiologically, parietal cells stimulate via 3 pathways to release acid into the stomach. These pathways are mediated by gastrin, histamine, and acetylcholine, respectively. Once stimulated, the parietal cells produce acid via an apical hydrogen-potassium adenosinetriphosphatase (ATPase), or the so-called proton pump. This enzyme releases hydrogen ions into the stomach in exchange for potassium ions, thus lowering the pH of the gastric lumen. This proton pump is the common final pathway for acid production.
Conceptually, acid secretion may be reduced by decreasing the stimulus to the parietal cell by blocking the gastrin-, acetylcholine-, or histamine-mediated pathway. No gastrin inhibitors are available currently. Anticholinergic agents are limited by their side-effect profile, including urinary retention, dry mouth, blurred vision, constipation, and cardiovascular toxicity. To date, only antagonists of the histamine pathway are clinically important.
H2 receptor antagonists were introduced in the late 1970s, and currently 4 agents are available: cimetidine, famotidine, nizatidine, and ranitidine (Table 3). All of these agents are available over the counter and are equal in efficacy when used at equivalent dosages. They are effective for the treatment of symptoms due to nonerosive reflux disease and for the healing of mild esophagitis. Higher doses of H2 receptor antagonists are required, however, for the treatment of more severe disease. At these high doses, the clinical and cost effectiveness of H2 blockers generally is surpassed by PPIs.1
H2 receptor antagonists are quite safe in patients of all ages. Mental status changes, however, have been described in elderly patients with both cimetidine and ranitidine, particularly in patients with renal and hepatic dysfunction. These effects may be more pronounced in patients with decreased renal function, a common feature of older populations. Famotidine and nizatidine are associated with fewer side effects in elderly patients but also must be dose-adjusted for renal function.25 Cimetidine is a cytochrome P-450 enzyme inhibitor and can affect the metabolism of a number of drugs, including warfarin, phenytoin, and theophylline.
PPIs are the newest and most effective of the modalities available for the treatment of GERD. They target the final pathway of acid secretion?the hydrogen- potassium ATPase. These agents are absorbed in the stomach and are presented to the parietal cells via the peripheral circulation. Once there, they bind irreversibly to the proton pump and permanently prevent the extrusion of hydrogen ions into the gastric lumen (ie, they prevent acid secretion). Acid secretion is maintained only by de novo synthesis of new proton pumps by the parietal cells. The irreversible binding of PPIs explains the dissociation between their relatively short half-life and their long duration of action, thus accommodating once-daily dosing for most patients.
Data from 33 randomized trials including more than 3000 patients with erosive esophagitis suggest that symptomatic relief can be expected in 27% of placebotreated, 60% of H2 receptor antagonist-treated, and 83% of PPI-treated patients. Esophagitis healing is seen in 24% of placebo-treated, 50% of H2 receptor antagonist-treated, and 78% of PPI-treated patients.26 PPIs eliminate symptoms and heal esophagitis more frequently and more rapidly than other agents.
Higher and more frequent dosing of H2 receptor antagonists improves efficacy but is still inferior to the effect of PPIs.27-29 This approach also has the disadvantage of multiple daily dosing. In the elderly, this requirement can be a particular problem. Additionally, PPI therapy has been shown to normalize the impaired QOL caused by GERD.30
Five PPIs currently are available in the United States: esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole (Table 4). All of these agents have been shown to control GERD symptoms and to heal esophagitis when used at equivalent dosages.1 These agents are particularly useful in elderly patients with GERD, who seem to require a greater degree of acid suppression than younger patients to heal their esophagitis.31-33 Additionally, single daily doses of PPIs have been shown to produce 67% to 95% symptom relief and healing of erosive esophagitis regardless of age, and both lansoprazole and omeprazole have been shown to maintain symptom relief and healing of esophagitis for up to 5 years.34,35 This duration, again, is important, because patients may require prolonged acid-suppression therapy to control symptoms and prevent complications. Prolonged acid suppression in elderly patients is required to minimize esophageal exposure to acidic gastric contents so that healing may begin and to prevent the development of complications. Recently, a formulation of omeprazole and sodium bicarbonate has been released to the market. The addition of bicarbonate protects the omeprazole component from the acid environment of the stomach, thus providing an "immediate-release" PPI formulation. The advantages of this approach have yet to be established.
The safety profile of PPIs is excellent. Although the renal clearance of PPIs is reduced in elderly patients, no reduction in the dose of either omeprazole or lansoprazole is needed in the elderly, including those with renal or hepatic dysfunction.36 The PPIs vary in the extent to which they are metabolized by the cytochrome P-450 system, and they may alter the metabolism of drugs such as warfarin. In patients taking warfarin, the use of newer PPIs may be preferred over omeprazole.36
There has been some concern that the profound acid suppression of PPIs may decrease the absorption of vitamin B12. This effect is secondary to the impaired secretion of intrinsic factor by parietal cells, which typically occurs in parallel with acid secretion. Intrinsic factor is needed for the absorption of vitamin B12 in the terminal ileum. Although this effect remains controversial, monitoring vitamin B12 levels periodically may be prudent with patients on long-term PPI therapy.3,36
Recently, some researchers have suggested that long-term PPI use may be associated with an increased frequency of fractures. A second issue regarding long-term acid suppression by PPIs or H2 blockers is a possible increase in the frequency of community-acquired pneumonia. Although there are data suggesting an association, it has not been shown in a randomized controlled trial. This potential risk must be weighed against the known benefits of acid suppression for appropriate indications. Another important concern with long-term PPI use has been the development of gastric carcinoid tumors because of hypersecretion of gastrin. The physiologic basis for this effect is that the normal feedback mechanism to decrease the secretion of gastrin is the low pH of the gastric lumen. By markedly inhibiting the production of acid, PPIs remove the negative feedback mechanism, resulting in promoting the release of gastrin. Gastrin, in turn, has the theoretical potential to stimulate the development of carcinoid tumors. Yet, there have been no reports of gastric carcinoid tumors in patients without an underlying predisposing syndrome.3
Surgical options also exist for the management of GERD. Laparoscopic fundoplication, whereby a portion of the stomach is surgically secured around the distal esophagus, is one of the more common procedures. The less invasive nature of this procedure has reduced the morbidity of anti-reflux surgery, but the short- and long-term outcomes of anti-reflux surgery are dependent on the experience and skill of the surgeon.
Interestingly, some data show similar morbidity, mortality, and hospital length of stay between elderly and younger patients who underwent surgical therapy.37 Most patients choose to pursue medical, rather than surgical, therapy for GERD symptoms. The presence of a hiatal hernia, however, may lead to a more careful consideration of surgical options.
The goals of GERD management in the elderly are similar to those for other age groups. They include elimination of symptoms, healing of esophagitis, management of complications, and maintenance of remission.3 There are 2 main approaches to drug therapy for GERD, referred to as the "step-up" and "step-down" approaches.38 In the step-up approach, therapy is initiated with relatively weak inhibition of acid secretion?for example, with an H2 receptor antagonist or a half-dosage PPI?subsequently titrated upward until symptoms are controlled. Conversely, in the step-down approach, therapy is initiated with the goal of maximum acid suppression?for example, with a full-dose PPI?titrated downward once symptom relief is attained to identify the lowest effective dosage.
This latter approach may be more rational in the elderly, based on the superiority of PPI across all grades of GERD and the suggestion that the elderly may require more intense acid suppression.3 Additionally, GERD symptoms may not be a reliable index of severity in the elderly?supporting the notion of step-down therapy.37 Some patients seem not to respond to standard, approved dosages of PPIs. In such cases, the use of higher doses divided and given twice daily is reasonable.1
A 68-year-old man with a medical history significant for long-standing "heartburn" presents to the pharmacy requesting assistance in choosing an OTC antacid for the control of his symptoms. On questioning by the pharmacist, he reports that he would like "something strong" because he is now having some difficulty swallowing solid foods. The most appropriate action is to:
Answer is at the end of the article.
Once therapy for GERD has been initiated, the clinician must monitor the patient for the efficacy of the therapy as well as for side effects, interactions, and complications. The efficacy of GERD therapy may be assessed by the monitoring of symptoms such as reflux, heartburn, and esophageal manifestations. Extraesophageal manifestations such as cough, hoarseness, and asthma also must be monitored, because these conditions are commonly associated with GERD, particularly in older patients.
It also is important to intermittently assess the patient for warning signs such as dysphagia, odynophagia, bleeding, weight loss, or evidence of anemia. The presence of warning symptoms should prompt evaluation by a physician (Table 5).
The pharmacist's role in the management of patients with GERD is multifaceted. When patients choose to treat their symptoms with OTC agents, it is important that the pharmacist discuss their symptoms with them to determine the appropriateness of OTC therapy and whether patients should be referred for formal evaluation. Symptoms that are severe, frequent, or of prolonged duration should prompt the pharmacist to have the patients present for evaluation. Likewise, the presence of warning symptoms necessitates evaluation. By referring patients, the pharmacist ensures that they receive appropriate care and are not exposed to the risks associated with OTC agents. For example, excessive OTC antacid use may be a particular problem in the elderly.
Pharmacists also may participate in the evaluation process by reviewing the medication profile for drugs that may be exacerbating the symptoms in question. When patients use OTC agents appropriately, the pharmacist should review their medication profile to ensure that they are not taking medications such as antibiotics (eg, fluoroquinolones), whose absorption may be altered by the use of OTC agents.
When promotility agents are used, pharmacists must monitor for mental status changes and motor side effects. As mentioned previously, H2 receptor antagonists also are associated with mental status changes and drug-drug interactions. Pharmacists must be vigilant in regard to these agents, as all 5 are available over the counter. Furthermore, in the appropriate setting, pharmacists can assist the health care team in ensuring that these agents are dosed appropriately for the patient's hepatic and renal function.
PPIs require much less monitoring, although vitamin B12 levels should be checked periodically in patients on longterm therapy. PPIs are most effective if given prior to meals (up to 30 minutes), due to the fact that only active proton pumps in the parietal cell are inhibited. After a meal, the window of opportunity is ~90 minutes, which is approximately the same as the half-life of most PPIs in the elderly. The prolonged duration of action of PPIs is due to the irreversible inhibition of proton pumps by PPIs. If taking the medication up to 30 minutes before or within 90 minutes after a meal is not practical, a reasonable compromise might be to take the agent at the beginning of a meal. Some data suggest that taking PPIs prior to breakfast provides maximal efficacy, although in cases where higher dosages are needed divided doses seem to be more efficacious.37 Pharmacists may include these recommendations when counseling patients regarding the use of PPIs so as to promote the maximal efficacy of the prescribed agent.
Alternative routes of administration may be needed in elderly patients due to difficulty in swallowing, intolerance of capsule or tablet formulations, or the use of feeding tubes. Both lansoprazole and omeprazole capsules can be opened and the granules taken with water, a bicarbonate-based suspension, or apple or orange juice, or the granules may be sprinkled on applesauce or yogurt.39 Additionally, lansoprazole is available as a dissolvable tablet (Prevacid Solutab) for oral or nasogastric tube administration.
A 68-year-old woman with a medical history of stable angina, hypertension, anxiety, and obesity presents to the pharmacy to refill her prescriptions, which include aspirin, isosorbide dinitrate, diazepam, metoprolol, simvastatin, and lisinopril. She also requests advice regarding management of GERD. After discussing her symptoms and verifying that they are consistent with GERD and that there are no warning symptoms present, the pharmacist reviews her medication profile. Which of the following agents is least likely to be contributing to her symptoms of GERD?
Answer is at the end of the article.
GERD is a common disease in both young and elderly patients. GERD can interfere markedly with patients' QOL. In addition, it entails a substantial economic burden related to the direct costs of diagnosis and treatment as well as the indirect costs related to absenteeism and decreased productivity. Elderly patients more often have atypical symptoms and present with more severe disease, and not uncommonly with complications. Consequently, it is important that health care professionals remain vigilant to detect GERD in this population.
A number of agents are available for the management of GERD, including antacids, promotility agents, H2 receptor antagonists, and PPIs. PPIs have been shown to be safe and effective in elderly patients with GERD and are associated with fewer side effects and interactions. Furthermore, their benefits have been shown to be sustainable for years. Consequently, PPIs usually are the agents of choice for the management of GERD in young and elderly patients.
Pharmacists have an important role in the identification of patients who need further evaluation and in the selection of therapy, as well as in monitoring efficacy, interactions, and side effects.
Case Study Answers:
Case 1: d
Quinn Wells, MD, PharmD, is an Internal Medicine Resident at Massachusetts General Hospital.