US Pharm. 2007(32):20-23.

 

Heartburn, one of the classic symptoms of gastroesophageal reflux disease (GERD), is a very common occurrence among the general population. In the United States, approximately 44% of the population experience symptoms of GERD monthly, while 20% have symptoms on a weekly basis.1 The prevalence of GERD increases with age in those 40 or older. The increased incidence of GERD in seniors remains unclear; however, changes in the antireflux mechanism that occur with age (e.g., less consistent esophageal peristalsis, decreased salivary response to esophageal acid infusion, etc.) may be responsible.2

Pyrosis (heartburn) and acid regurgitation (passage of gastric contents into the oropharynx) secondary to chronic reflux are the classic symptoms of this disorder. Excessive reflux of acidic gastric contents into the esophagus, resulting in irritation or injury to the esophageal mucosa, constitutes a diagnosis of GERD. Interestingly, according to the American College of Gastroenterology guidelines, while the presence of esophagitis or Barrett's esophagus is diagnostic for GERD, normal endoscopy results are found in the majority of symptomatic patients and neither rule out GERD nor indicate a lower severity of symptoms.3 The guidelines further state that such patients with so-called "endoscopic negative" disease have similar requirements for therapy and should receive the same treatment considerations as patients who have erosive esophagitis, including, in some patients, long-term proton pump inhibitor (PPI) therapy.

Success of GERD Treatment
The goals of therapy for GERD are to: 1) alleviate or eliminate symptoms; 2) decrease frequency or recurrence and duration of GERD; 3) promote healing of mucosa; and 4) prevent complications. The PPIs are more effective than histamine2 -receptor antagonists (H2RAs) in achieving these goals of therapy. They are capable of providing complete resolution of symptoms and healing of esophagitis. Healing rates after four weeks and eight weeks of therapy are approximately 80% and 90%, respectively, with PPIs (esomeprazole [Nexium], lansoprazole [Prevacid], omeprazole [Prilosec], pantoprazole [Protonix], rabeprazole [Aciphex]) as compared to approximately 50% and 75%, respectively, with H2RAs (cimetidine [Tagamet], famotidine [Tagamet], nizatidine [Axid], ranitidine [Zantac]).4

Clinical Features
Often, there is a lack of heartburn in an elderly patient with GERD. While the severity of symptoms in this population may be decreased, this does not indicate lack of esophagitis. In fact, older people are more likely to develop severe disease. Atypical symptoms may manifest outside the intestinal tract (TABLE 1) as cough, wheeze associated with asthma, noncardiac chest pain, dental deterioration, jaw pain, and anemia.5,6 Alarm symptoms of GERD require immediate medical attention; these include dysphagia, odynophagia, choking, bleeding, weight loss, and chest pain. GERD is also associated with specific respiratory conditions including bronchitis, laryngopharyngitis, refractory asthma, and aspiration pneumonia.7 Furthermore, since severity of symptoms often does not correlate with the degree of esophagitis, it has been recommended that all elderly patients experiencing onset of symptoms be considered for diagnostic endoscopy.2



GERD is often poorly diagnosed and underreported in the geriatric population since seniors typically present with atypical symptoms, as noted above. Differentiation from other disease states such as asthma and angina is required. Acid suppressant therapy is important in this population since seniors are less likely to report frequent or severe heartburn secondary to a decline in esophageal sensitivity. In addition, seniors are at increased risk for GERD-associated bleeding if they take daily aspirin, antiplatelet agents, anticoagulants, NSAIDs, and selective serotonin reuptake inhibitors.8 Since the elderly are at higher risk for infection, are particularly susceptible to the respiratory complications of GERD, and are a population for whom pneumonia is a major cause of mortality, the need for acid-suppressant therapy is clear in appropriate candidates.9

 

Current Treatment Philosophy

In general, the current treatment philosophy for acid suppression is divided into phases. Phase I involves lifestyle modifications (e.g., dietary changes [avoidance of foods that decrease lower esophageal sphincter pressure or are direct irritants], weight reduction, smoking cessation, head-of-bed elevation [6-8 inches], avoiding eating three hours before bedtime, avoiding tight-fitting clothes) and OTC antacids or low-dose H2RAs.1 Phase II involves the use of lifestyle modifications, and prescription H2RAs or PPIs. Finally, phase III involves intervention therapies (e.g., surgery). For seniors, the step-down approach (starting at phase II) is recommended. This involves initiating the most effective regimen, which is a full dosage of a PPI, and, once symptoms are under control, switching to lower doses of the PPI for maintenance therapy.10 This approach may be more rational, compared to the step-up (starting at phase I) approach, based on the evidence showing superior efficacy of PPIs over H2RAs across all grades of GERD severity. No comparative studies have evaluated whether the step-down or step-up approach is more cost effective in elderly patients. 10  PPI therapy does not require dosage adjustment for renal insufficiency, as compared with H2RAs, often an issue in the elderly.

Refractory Symptoms and Nocturnal Acid Breakthrough
Severe symptoms or extraintestinal manifestations may require twice-daily PPI dosing, with two-thirds of patients continuing to make acid, particularly at night. This is called nocturnal acid breakthrough.4 Clinicians should become familiar with the symptoms associated with nighttime reflux (TABLE 2 ) so that recognition may be facilitated.  Refractory symptoms on twice-daily PPI therapy are often treated with the addition of an H2 RA at night (with short-lived effect secondary to tolerance development). 4,10,11 In the refractory patient, additional testing should be considered to exclude complications, and the diagnosis may need to be changed. Since sleep is a significant risk factor for acid migration to the proximal esophagus and markedly prolongs acid clearance, nighttime reflux may increase the risk of microaspiration.12 In fact sleep--particularly sound sleep--may represent risk for adverse physiologic events.13



Apparently Refractory Reflux Disease: Approach to Therapy
In refractory patients, it is recommended that the clinician verify adherence with lifestyle modifications and assess adherence with PPI therapy. Making certain that the patient is taking the daily PPI dose before the first meal of the day is essential. Additionally, pharmacotherapy adjustments may need to be made: 1) use maximum FDA-labeled dosage; 2) increase PPI dose to twice daily (e.g., off-label use may be required in some situations) with administration of the second dose 30 minutes prior to evening meal, not at bedtime; 3) use of on-demand PPI therapy may be suitable for patients with mild to moderate symptoms (however, studies are lacking); 4) patients who have tried less effective medications without success should have access to long-term PPI therapy; 5) add a prescription-strength H2RA at night; 6) add an OTC H2RA (e.g., ranitidine 75 mg) 30 to 60 minutes before eating/drinking items causing heartburn; and, finally, 7) if patient remains refractory to therapy, refer to specialist.4,10,14 It is important to bear in mind that acid is usually unlikely to be the cause of symptoms with twice-daily dosing of a PPI. Response to aggressive acid suppression is often the most commonly employed initial tool to indicate GERD etiology in a patient with atypical symptoms.

GERD and the Asthma Patient
GERD has recently been recognized as a common trigger of asthma, potentially via esophageal acid-induced reflex bronchoconstriction and microaspiration of acid.15 In addition, allergic rhinitis (AR) coexists with asthma, although it is unknown whether asthma and AR are different manifestations of an allergic process or if AR is a discrete asthma trigger.15 In a recent study, more than 50% of patients with difficult-to-treat asthma were diagnosed with GERD with evidence indicating the important role of acid reflux in patients who have problems controlling their asthma.16 This is an important concept since there are approximately 5,000 deaths in the U.S. per year attributable to asthma, with most cases classified as preventable with treatment.15 Furthermore, the prognosis of asthma is good with adequate access and adherence to treatment; appropriate treatment for acute exacerbations and chronic asthma is required.

GERD in the asthma patient may require higher dosages and a longer course of treatment as compared to patients with classic symptoms.4 Initial empiric therapy with twice-daily PPIs for two to three months is generally recommended.

Potential Risks with Acid-Suppressant Therapy
There have been some concerns and controversies regarding the use of acid-suppressant therapy. PPIs have been associated with gastric carcinoid tumors observed in rats but have not been demonstrated in humans.17 According to one case-controlled study looking at patients older than 50, long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture, possibly due to interference with calcium absorption through induction of hypochlorhydria and may potentially reduce bone resorption.18 Another case-controlled study found support of an association between chronic use of H2RAs and PPIs by older adults and the development of vitamin B12 deficiency. While additional studies are needed to confirm these findings, it is an important consideration as vitamin B12 deficiency is a common problem among the elderly.19 Acid suppression with H2RAs and PPIs is associated with an increased risk of community-acquired pneumonia, probably due to a reduction of gastric acid secretion that facilitates oral infections.20 This finding is a dose-response effect with the relative risk of pneumonia modest with H2 RAs, greater with PPIs, and greatest with more than once-daily dosing of a PPI. 20 The researchers recommended that immunocompromised, asthmatic, COPD, pediatric, and elderly patients should be treated only when needed and with the lowest effective dosage.

Conclusion
For the senior and senior refractory patient with GERD, careful consideration of acid-suppression therapy is recommended due to: atypical symptoms, increased risk of infection, increased risk of mortality secondary to pneumonia, and risk-associated medications in the regimen. Clinicians, health care administrators, and providers need to understand the importance of balancing the benefit of appropriate and adequate PPI therapy with pharmacoeconomic and long-term safety concerns. In light of the favorable safety profile, ease of administration, potential risks of therapy, and high rate of effectiveness of PPI therapy, long-term therapy is beneficial for chronic or complicated GERD, and higher-than-approved dosages may be appropriate in certain situations. Furthermore, unnecessary human and health care costs may potentially be avoided with the appropriate treatment of GERD, a known trigger of asthma.

 

References
1. Williams DB, Schade RR. Gastroesophageal reflux disease. In: Dipiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. Appleton & Lange, 2005:613-628.
2. Hila A, Castell DO. Upper gastrointestinal disorders. In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York: McGraw-Hill, Inc.; 2003:622-626.
3. Updated ACG Guidelines for Diagnosis and Treatment of GERD. The American College of Gastroenterology (ACG). Available at: www.acg.gi.org/physicians/guidelines/ GERDTreatment.pdf. Accessed October 1, 2007.

4. Hoogerwerf WA, Pasricha PJ. Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux disease. In: Brunton, et al., eds. Goodman & Gilman's; 2006: 976-978.

5. Greenwald DA. Aging, the gastrointestinal tract, and risk of acid-related disease. Am J Med. 2004;117(suppl 5A):8S-13S. 

6. Johnson DA. Gastroesophageal reflux disease in the elderly--a prevalent and severe disease. Rev Gastroenterol Disord. 2004;4(suppl 4):S16-24.

7. Sataloff RT, Castell DO, et al. Reflux Laryngitis and Related Disorders. 2nd ed. New York, NY: Delmar Thomson Learning; 2003.

8. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 12th ed. Hudson, Ohio: Lexi-Comp, Inc.; 2007.

9. Zagaria ME. GERD: Maximizing Outcomes in Special Populations. In: Strategies for Optimal Disease Management in Patients with GERD. Presented in association with the Academy of Managed Care Pharmacists; Hynes Convention Center, Boston Massachusetts; October 25, 2007.

10. Pilotto A, Franceschi M, Paris F. Recent advances in the treatment of GERD in the elderly: focus on proton pump inhibitors. Int J Clin Pract. 2005;59:1204-1209.  

11. Winter HS, Gold BD, Nelson SP. Pediatric GERD: a problem-based approach to understanding treatment. 2005. Medscape. Available at: www.medscape.com/viewprogram/4715. Accessed October 22, 2007.

12. Orr WC, Elsenbruch S, Harnish MJ, et al. Proximal migration of esophageal acid perfusions during waking and sleep. Am J Gastroenterol. 2000;95:37-42.

13. Orr WC. Sleep issues in gastroesophageal reflux disease: beyond simple heartburn control. Rev Gastroenterol Disord. 2003;3(suppl 4):S22-S29.

14. Vaezi MF. Atypical manifestations of gastroesophageal reflux disease. Medscape General Medicine. Available at: www.medscape.com/viewarticle/506303_print. Accessed October 1, 2007.

15. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:112-113.

16. Wong CH, Chua CJ, Liam CK, et al. Gastro-oesophageal reflux disease in ‘difficult-to-control' asthma: prevalence and response to treatment with acid suppressive therapy. Aliment Pharmacol Ther. 2006;23:1321-1327.

17. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:323-329.

18. Yang YX, Lewis JD, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2954.

19. Valuck RJ, Rusein JM. A case-controlled study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol . 2004;57:422-428.

20. Laheij RJ, Sturkenboom MC, Hassing RJ, et al.  Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955-1960.

21. Hogan WJ, Shaker R. Supraesophageal complications of gastroesophageal reflux. Dis Mon. 2000;46:193-232.

22. Gislason T, Janson C, Vermeire P, et al. Respiratory symptoms and nocturnal gastroesophageal reflux: a population-based study of young adults in three European countries. Chest . 2002;121:158-163.

 

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