Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL OPTIONS in Gastroenterology

Reviews from published literature - March 2009

Towards Improved Treatment Outcomes: Revisiting GERD Symptomatology

Dr. David Armstrong, McMaster University

Proton Pump Inhibitors in the Elderly: Special Considerations

Dr. Gilbert Doummar. Centre hospitalier Pierre-Boucher

Current Strategies for Prophylaxis Against NSAID-induced Upper Gastrointestinal Injury

Dr. Richard H. Hunt, McMaster University

Generic PPIs: Are They Equivalent to the Original Formulations?

Dr. Peter J. Lin, Canadian Heart Research Centre

TOWARDS IMPROVED TREATMENT OUTCOMES : REVISITING GERD SYMPTOMATOLOGY

Editorial Overview:

David Armstrong, MA, MB BChir, FRCP(UK), FACG, AGAF, FRCPC

Associate Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Ontario

Despite the high rates of efficacy associated with proton pump inhibitors (PPIs), there is a substantial minority of patients with gastroesophageal reflux disease (GERD) who are not fully controlled on standard doses. Symptom assessment with objective but simple questionnaires, such as the Proton Pump Inhibitor Acid Symptom Suppression (PASS) test, provides an important opportunity to detect and assess inadequate symptom control, adjust patient management and improve quality of life. Incorporation of such tests into routine clinical practice demonstrates that an initial reduction in symptoms achieved with PPIs does not necessarily constitute optimal or even acceptable symptom control for many patients. Typically chronic, GERD may have a variable course, requiring periodic reassessment in order to confirm continued symptom control or to identify worsening symptoms that require adjustment of therapy to restore acceptable control.

Addressing Residual or Recurrent Symptoms

The relatively high rates of treatment success achieved with PPIs for control of acid-related symptoms, including the heartburn associated with GERD, may explain why physicians tend to overestimate the efficacy of this drug class.¹ In the empirical treatment of upper gastrointestinal (GI) complaints, symptom reduction in response to PPI therapy can serve to confirm the diagnosis of an acidrelated disorder; a prompt, readily-identifiable response encourages both the physician and the patient to consider that the clinical problem has been resolved, even if symptoms have not been abolished. Cases of persistent residual or recurrent symptoms in the presence of standard PPI therapy may be overlooked based on the improvement in symptoms and the presumption that optimal therapy has already been prescribed even when quality of life remains significantly impaired.

Complete or near complete symptom control is a reasonable goal in all or most patients with acid-related upper GI symptoms. Standard doses of PPIs are an appropriate first-line therapy for persistent heartburn or dyspepsia, but alternative regimens should be considered when symptom relief is inadequate. This may include switching to a different PPI, dividing the daily PPI dose so that it is taken twice daily and doubling the standard PPI dose. Patients should also be encouraged to make lifestyle changes, as needed, such as avoiding late night meals or diets that precipitate symptoms.

The evidence that a substantial minority of patients continues to experience symptoms on standard doses of PPIs can be drawn from several sources. Most conspicuously, up to 20% of patients already take PPIs at twice the standard dose.² In addition, up to 50% of patients on PPIs also take over-thecounter (OTC) medications, such as antacids, for supplemental symptom relief.³ In a survey of 1064 patients sponsored by the American Gastroenterological Association (AGA), 40% of patients taking a PPI for GERD reported that they had persistent symptoms (>2 episodes per week).⁴ Of these, 40% had not discussed the symptoms with their physician. The survey also found that 57% of patients on a PPI had not been asked by their physician about their use of OTC therapies to improve symptom control.

Table 1.

In patients with an initial reduction in symptoms on PPIs, the relevance of residual or recurrent symptoms to the underlying acidrelated disorder may be difficult to interpret. Almost all individuals have occasional episodes of heartburn, and the significance that patients assign to these episodes varies. In determining whether current therapy is adequate, the most important criterion is whether persistent pain or discomfort has an adverse effect on activities of daily living, including sleep, eating or a sense of wellbeing. Simple questions about well-being may elicit adequate information to alter therapy, but there are obvious advantages to using a standardized and reproducible methodology that enables clinicians to gauge the patient’s response to treatment modifications.

PASS: A Simple Tool for Clinicians

Numerous structured evaluations have demonstrated reproducibility for evaluating GERD symptoms, but most have been developed for research purposes, are cumbersome in clinical practice, and were not created specifically to evaluate persistent symptoms in patients with established GERD who are already taking therapy. In the context of the frequency of persistent GERD in patients on a PPI, a practical methodology for clinical use is warranted. To address this need, a multicentre Canadian collaboration produced the PASS test (Table 1), which has been validated in both English and French versions.⁵ This test, which was developed initially for GERD patients receiving a PPI, is completed with responses to five yes-or-no questions.

In the initial validation phase, the PASS test demonstrated good reliability and moderate to high correlation with the Gastrointestinal Symptom Rating Scale (GSRS). Thus, the PASS test can be employed to document clinically significant persistent symptoms on PPI therapy and to evaluate response to treatment modification. Initial studies, in which PASS-positive patients were evaluated after a switch in PPI therapy, showed that 32% of the patients had a total resolution of symptoms four weeks after being switched to a regimen that offered greater acid suppression (Figure 1). The validated PASS test was able to confirm that a substantial proportion of patients with persistent symptoms can impro
herapy.

Figure 1.

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There are numerous reasonable options for improving symptom control in patients with persistent symptoms on PPI therapy. In the aforementioned validation study of PASS, patients were switched to esomeprazole, a PPI which has demonstrated greater 24-hour acid control than alternative PPIs in controlled studies. Although the PASS validation study was open-labelled and not designed to show that esomeprazole was superior to alternative PPIs for symptom control, its greater acid control does confer an advantage for healing of esophagitis—an objective, endoscopicallycontrolled outcome—in double-blind trials against all of the PPIs to which it has been compared (omeprazole, lansoprazole and pantoprazole).^6-8 It has also shown greater efficacy than lansoprazole or pantoprazole for preventing recurrence of erosive esophagitis.^9,10

Strategies for Controlling Acid Reflux

The direct correlation between degree of acid control and likelihood of healing has been well established.¹¹ Although there is a relatively poor relationship between symptoms and the presence or healing of esophagitis,¹² the fundamental importance of acid to symptoms is well accepted. Even though patients with GERD or heartburn do not necessarily demonstrate greater gastric acid secretion than those without upper GI symptoms, pH monitoring can correlate episodes of acid reflux into the esophagus with symptom onset.¹³ This is true in patients with non-erosive reflux disease (NERD) as well as in patients with esophagitis.

In patients with persistent symptoms, switching to the most effective PPI for acid control is a reasonable strategy. In a meta-analysis of PPI comparative trials, esomeprazole provided an 8% relative increase (RR 1.08; 95% CI, 1.05-1.11) in healing at eight weeks.¹⁴ The greater healing rates achieved with esomeprazole can be reasonably attributed to greater acid control.

For patients whose symptoms are not controlled by a single daily PPI dose, dividing the dose or doubling the daily dose by adding an evening pill are appropriate strategies, particularly in patients with significant nocturnal symptoms. Just as the morning dose should be given prior to breakfast, the evening dose should be administered prior to the evening meal. Meal stimulation of the acid pumps promotes retention and binding of the active drug in the parietal cells’ secretory canaliculi, thereby optimizing inhibition of proton pump activity. Cost rather than safety may be the more important determinant of whether to divide or double the dose of PPI, compared with a standard regimen. In general, tolerability of twice-daily standard doses of PPIs is similar to that observed in once-daily dosing.¹⁵

The close correlation between acid control and healing of esophagitis is the basis for considering the most potent PPI as the firstline therapy, particularly as endoscopic studies to confirm the presence or healing of esophagitis are not indicated as part of routine care in patients who have no alarm symptoms or increased risk of complications. However, symptom control is a valid and important end point on its own. Persistent heartburn imposes large decrements in quality of life even among patients who accept symptoms as an unavoidable burden. With the availability of effective strategies to relieve symptoms, clinicians should accept a responsibility not only to ask about the frequency and severity of heartburn but also periodically to re-evaluate symptom expression.

Summary

The efficacy of PPI therapy against GERD is sufficiently reliable that response to a PPI is considered diagnostic. However, the substantial minority of patients who do not achieve adequate symptom relief on standard doses of PPIs is not well recognized. Although a PPI, at a conventional dose, is the first-line treatment for GERD,¹⁶ patients should be specifically questioned about symptom control after initiating therapy and periodically thereafter in follow-up of what is typically a chronic disease.¹⁷ PPIs are not necessarily equivalent in efficacy for the treatment of GERD because of differences in intragastric acid control over each 24-hour period. However, in patients who do not respond to a standard dose of the most potent PPI, other strategies, particularly double-dose regimens, should be considered with the goal of complete or near complete symptom control.

References

1. Fallone et al. Do physicians correctly assess patient symptom severity in gastro-oesophageal reflux disease? Aliment Pharmacol Ther 2004;20:1161-9.

2. Abu Farsakh N. Symptomatic and endoscopic outcome of heartburn 3-4.5 years after starting lansoprazole therapy: a prospective study of 142 patients. J Gastroenterol 2003;38:1042-8.

3. Jacobson et al. Who is using chronic acid suppression and why? Am J Gastroenterol 2003;98:51-8.

4. American Gastroenterological Association. AGA News release: Nearly 40% of GERD patients taking PPIs experience recurring symptoms. www.gastro.org/ wmspage.cfm?parm1=5287. Accessed Jan 2, 2008.

5. Armstrong et al. Validation of a short questionnaire in English and French for use in patients with persistent upper gastrointestinal symptoms despite proton pump inhibitor therapy: the PASS (Proton Pump Inhibitor Acid Suppression Symptom) test. Can J Gastroenterol 2005;19:350-8.

6. Richter et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96:656-65.

7. Castell et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575-83.

8. Labenz et al. A randomised comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive esophagitis: the EXPO study. Aliment Pharmacol Ther 2005;21:739-46.

9. Devault et al. Maintenance of healed erosive esophagitis: a randomized six-month comparison of esomeprazole 20 mg and lansoprazole 15 mg. Clin Gastroenterol Hepatol 2006;4:852-9.

10. Labenz et al. Esomeprazole 20 vs. pantoprazole 20 mg for maintenance therapy of healed erosive oesophagitis: results from the EXPO study. Aliment Pharmacol Ther 2005;22:803-11.

11. Bell et al. Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 1992;51(suppl1):59-67.

12. Johnsson et al. Symptoms and endoscopic findings in the diagnosis of gastroesophageal reflux disease. Scand J Gastroenterol 1987;22:714-8.

13. Madan et al. Impact of 24-h esophageal pH monitoring on the diagnosis of gastroesophageal reflux disease: defining the gold standard. J Gastroenterol Hepatol 2005;20:30-7.

14. Gralnek et al. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol 2006;4:1452-8.

15. Wilder-Smith et al. Acid control with esomeprazole and lansoprazole: a comparative dose-response study. Scand J Gastroenterol 2007;42:157-64.

16. Armstrong et al. Canadian Consensus Conference on the management of Gastroesophageal Reflux Disease in adults - update 2004. Can J Gastroenterol 2005;19(1):15-35.

17. Armstrong D. Systematic review: persistence and severity in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2008;28(7):841-53.

PROTON PUMP INHIBITORS IN THE ELDERLY: SPECIAL CONSIDERATIONS

Editorial Overview:

Gilbert Doummar, MD, FRCPC

Head, Department of Gastroenterology, Centre hospitalier Pierre-Boucher, Longueuil, Quebec

The likelihood that patients presenting with heartburn will also have underlying esophagitis increases with age. The challenge for the clinician is that there is a poor correlation between severity of heartburn and the presence of esophagitis, particularly in older individuals who demonstrate diminishing sensitivity to upper gastrointestinal (GI) complaints. The increased frequency with which mild symptoms are accompanied by significant esophageal lesions in the elderly is further complicated by an increased likelihood of atypical symptoms, an increased risk of complications stemming from inadequately controlled gastroesophageal reflux disease (GERD), and an increased risk of comorbidities that must be managed concurrently with GERD. The specific characteristics of GERD in the elderly demand management adjusted to increase the likelihood of esophagitis healing and reduce the risk of complications in this age group.

Complications from GERD

The proportion of individuals in Canada and other Western countries with GERD symptoms of sufficient severity and frequency to impair quality of life is estimated to range between 10% and 20%.¹ Although the prevalence of GERD may be somewhat higher in the elderly than in younger individuals,^2,3 the presentation of GERD in older individuals is characterized by a substantially greater risk of underlying esophagitis. While less than half of patients with heartburn younger than age 60 have underlying esophagitis, rates as high as 80% have been reported in patients older than age 60 (Figure 1).⁴ Unsurprisingly, the rates of the most significant complications of GERD, such as Bar
also greater in the elderly.⁵

Figure 1.

<img2923|center>

Symptom severity is not an accurate indicator of underlying esophageal lesions in patients of any age, and the relationship is particularly weak in the elderly.⁶ Even among patients with the most severe forms of esophagitis, Barrett’s esophagus, or esophageal adenocarcinoma, the elderly are even more likely than younger patients to report few or mild symptoms,⁷ a phenomenon that may be linked to a diminished pain sensitivity in the upper GI tract observed in the elderly.⁸ The greater risks of complications from GERD, including Barrett’s esophagus and adenocarcinoma of the esophagus, increase the relative importance of an accurate diagnosis and appropriate therapy.^9,10

Atypical Symptoms and Recommendations

Due to the frequency of GERD and its risks, elderly patients should be routinely questioned about digestive health. In considering a diagnosis of GERD, it is particularly important to be sensitive to the presence of atypical symptoms in the elderly. Although classic presentations of heartburn are not uncommon, functional dyspepsia, persistent laryngitis or hoarseness, globus, loss of appetite, or nausea may also serve as initial manifestations of GERD, particularly in the elderly. In patients with a previous history of GERD who have a change in symptom expression or severity or in patients who are reporting symptoms consistent with GERD for the first time, it is appropriate to elicit a careful history focused on recent changes in medications, eating or other life habits, or life stress. An evaluation of alarm symptoms, particularly unexplained weight loss, dysphagia, or hematemesis, should be conducted in consideration of etiologies other than GERD.

In patients without alarm symptoms, a trial of a proton pump inhibitor (PPI) is valuable both as an immediate step toward symptom relief and as a diagnostic tool to demonstrate that symptoms are acid-related. In responders, an endoscopic evaluation is not urgent. However, an endoscopic examination should be performed within months of initiating treatment in elderly patients because of the increased potential for significant complications. Although patients with mild to moderate esophagitis may have healed within this treatment period, endoscopy permits screening of other pathologies, such as persistent esophagitis and Barrett’s esophagus.

Due to the increased risk of esophagitis and its complications, elderly patients with chronic GERD should be maintained on full doses of PPI therapy. Although PPI therapy may be augmented with lifestyle modifications, such as avoiding meals close to bedtime, these should be considered adjuctive steps toward symptom control. Similarly, antacids or H₂-receptor antagonists may be combined with PPIs as needed to achieve adequate symptom relief, but these should not be substituted for PPIs, particularly in the elderly, because they are ineffective for lesion healing. Although H₂-receptor antagonists have produced healing rates as high as 45% after 12 weeks of therapy, the likelihood of healing diminishes with the severity of esophagitis even with longer treatment courses.¹¹ The difference between H₂- receptor antagonists and PPIs can be explained by more complete acid control over each dosing period.¹²

Increasing Severe Esophagitis Healing

The same principle explains differences in efficacy between PPIs. There have now been several large, multicentre studies comparing PPIs for 24-hour acid control and for healing of esophagitis. In both sets of studies, the S-isomer of omeprazole, esomeprazole, has demonstrated a relative advantage over alternative PPIs. The ability of esomeprazole to maintain the gastric pH >4 over a greater proportion of each 24-hour dosing period, which has been demonstrated over every other currently available PPI,¹³ explains its advantage for healing in direct comparison studies with omeprazole,¹⁴ lansoprazole¹⁵ and pantoprazole.¹⁶

In each of the randomized studies, the significant healing advantage of esomeprazole over a comparator PPI has increased with increasing esophagitis severity. While differences were modest for the lowest grade of esophagitis, the stepwise increase in the healing advantage produced large differences at the highest grades of severity. In a meta-analysis of the comparative trials, the calculated number needed to treat (NNT) to achieve an additional healed patient was 50 for Los Angeles e
ade A, 33 for grade B, 14 for grade C, and only 8 for grade D (Figure 2).¹⁷

Figure 2.

<img2927|center>

These differences in healing have particular relevance for the elderly due to the increased likelihood of esophagitis and the greater chance of developing complications. Moreover, the same relative advantage is observed when PPIs are compared for maintenance therapy to prevent recurrence of esophagitis. For example, in a maintenance extension that followed the healing phase of a comparison of 40 mg q.d. esomeprazole to 40 mg q.d. pantoprazole, symptomatic remission at six months was maintained in 87% of those receiving 20 mg q.d. esomeprazole vs. 74.9% of those receiving 20 mg q.d. pantoprazole (P<0.0001).¹⁸ A comparable advantage for esomeprazole relative to lansoprazole was observed in a maintenance comparison of these PPIs.¹⁹

The Case for Chronic PPI Treatment

Due to the increased likelihood of esophagitis in elderly patients, on-demand maintenance therapy to control symptoms is not appropriate. The increased risk of complications and the potential for intermittent acid control to permit esophagitis to persist argues for chronic treatment regimens. Again, initiating therapy with the most potent PPI is particularly important in the elderly because esophagitis may persist in the absence of symptoms, while endoscopic evaluations to confirm healing are expensive and impractical. PPIs other than esomeprazole, which are metabolized differently and have modest differences in their risk for drug-drug interactions, should be tried in instances of intolerability.

PPI therapy is remarkably safe in the elderly as it is in other age groups. High degrees of tolerability and safety are particularly welcome in the elderly, who frequently have comorbidities and an increased susceptibility to side effects. Although two recent case control studies raised concerns about a possible association between PPI use and hip fracture,^20,21 the risk was low and efforts to identify a plausible biological mechanism, such as interference with calcium metabolism, have not been convincing. Based on inconsistencies in the data and the very low risk even if risk calculations are accurate, a position paper by the Canadian Association of Gastroenterology (CAG) advised no particular care in prescribing PPIs even among those with established osteoporosis.²² The paper noted that PPIs remain one of the most well tolerated drug classes used in clinical medicine.

The diagnosis and management of GERD in the elderly is often complicated by the presence of comorbidities. Symptoms of GERD must be differentiated from a wide variety of causes, including upper GI symptoms associated with medications that are being taken for other conditions. Efforts to confirm a diagnosis of GERD are warranted because of the important opportunity to improve quality of life. There are substantial data to demonstrate that persistent GERD can impair activities of daily living and quality of sleep independent of the risks it poses for complications.²³ A trial of PPI therapy in a patient suspected of GERD is a simple and effective method of confirming an acidrelated source of symptoms, but symptom relief is not an isolated goal because of the risk of underlying esophageal lesions.

Summary

GERD is a common disorder in individuals of all ages, but it poses special risks in the elderly. Although symptoms of GERD may be modest in the elderly relative to younger individuals, the risks of esophagitis and the complications of GERD, including Barrett’s esophagus and esophageal adenocarcinoma, are greater. PPIs are first-line therapy for GERD regardless of patient age, but the difference in the relative efficacy in PPIs may be particularly important in the elderly. In large, randomized trials, the greater acid control of esomeprazole has been repeatedly associated with greater healing, particularly for the most severe grades of esophagitis, which occur with greater frequency in the elderly and, in turn, are associated with the greatest risk of complications.

References

1. Dent et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710-7.

2. Mold et al. Prevalence of gastroesophageal reflux in elderly patients in a primary care setting. Am J Gastroenterol 1991;86:965-70.

3. Maekawa et al. Relationship between severity and symptoms of reflux esophagitis in elderly patients in Japan. J Gastroenterol Hepatol 1998;13:927-30.

4. Collen MJ, Abdulian JD, Chen YK. Gastroesophageal reflux disease in the elderly: more severe disease that requires aggressive therapy. Am J Gastroenterol 1995;90:1053-7.

5. Eloubedi MA, Provenzale D. Clinical and demographic predictors of Barrett’s esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol 2001;33:306-9.

6. Johnson DA, Fennerty MB. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology 2004;120:660-4.

7. Triadafilopoulos G, Sharma R. Features of symptomatic gastroesophageal reflux disease in elderly patients. Am J Gastroenterol 1997;92:2007-11.

8. Lasch H, Castel DO, Castell JA. Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension. Am J Physiol 1997:272:G1-G3.

9. Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett’s esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol 2001;33:306-9.

10. Voutilainen et al. Gastroesophageal reflux disease: prevalence, clinical, endoscopic, and histopathological findings in 1,128 patients referred for endoscopy due to dyspeptic and reflux symptoms. Digestion 2000;61:6-13.

11. Klinkenberg-Knol EC, Festen HPM, Meuwissen SGM. Pharmacological management of gastro-oesophageal reflux disease. Drugs 1995;49:695-710.

12. Chiba et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a metaanalysis. Gastroenterology 1997;112:1798-810.

13. Miner et al. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003;98:2616-20.

14. Richter et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96:656-65.

15. Castell et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575-83.

16. Labenz et al. A randomised comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive esophagitis: the EXPO study. Aliment Pharmacol Ther 2005;21:739-46.

17. Gralnek et al. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol 2006;4:1452-6.

18. Labenz et al. Esomeprazole 20 mg vs. pantoprazole 20 mg for maintenance therapy of healed erosive esophagitis: results from the EXPO study. Aliment Pharmacol Ther 2005;22:803-11.

19. Lauritsen et al. Esomeprazole 20 mg and lansoprazole 15 mg in maintaining healed reflux esophagitis: Metropole study results. Aliment Pharmacol Ther 2003;17:333-41.

20. Yang et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53.

21. Targownik et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319-26.

22. Moayeddi P and CAG Clinical Affairs Committee. CAG Position Statement: Hip fracture and proton pump inhibitor therapy. Available at www.cag-acg.org/ uploads/guidelines/cag position - ppi & hip fracture. pdf. Accessed Jan 2, 2009.

23. Ronkainen et al. Gastro-oesophageal reflux symptoms and health-related quality of life in the adult general population – the Kalixanda study. Aliment Pharmacol Ther 2006;23:1725-33.

CURRENT S TRATEGIES FOR PROPHYLAXIS AGAINS T NSAID-INDUCED UPPER GASTROINTESTINAL INJURY

Editorial Overview:

Richard H. Hunt, MD, FRCP, FRCPC, FACG, AGAF

Farncombe Family Institute of Digestive Health Research Institute, McMaster University Health Science Centre, Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Ontario,

In Canada and other industrialized countries, more than one-third of the population over the age of 65 take NSAIDs or ASA regularly to control chronic inflammatory conditions or to reduce cardiovascular (CV) risk. These agents substantially increase the risk of gastrointestinal (GI) complications in both the upper and lower tracts. In this analysis of strategies for risk management in the upper GI tract, an emphasis will be placed on recognizing competing risks. For example, the initial enthusiasm for the reduced GI risk of COX-2 selective NSAIDs was modified when an increased risk of CV events resulted in the withdrawal of several agents in this class. Low-dose ASA therapy, a common strategy for reducing CV risk, increases the risk of GI and cerebrovascular bleeds, requiring clinicians to consider the relative risk of each. Proton pump inhibitors (PPIs) can reduce the risk of GI bleeding associated with non-selective NSAIDs, but patients considered to be at high risk of a GI bleed may be best managed by combining a COX-2 inhibitor with a PPI. In patients at high CV risk, ASA may be required, and in those at the highest CV risk, both COX-2 selective and non-selective NSAIDs should be avoided. Greater appreciation of the balance required between health risks in aging is a critical element for appropriate individualization of risk management strategies in these patients.

Relative Risk of Chronic NSAID Therapy

The annual incidence of significant GI complications, such as serious bleeding, perforation or obstruction while on chronic NSAID therapy, is estimated at 1% to 2%,¹ and climbs to 4% to 5% when clinically significant ulcers are added.² These risks are substantial because of the high population exposure to NSAIDs. Among individuals over the age of 65, a group at increased risk for GI complications from NSAIDs, 20% of Canadians were prescribed an NSAID in the year 2000.³ Use of over-the-counter (OTC) NSAIDs likely increases substantially the proportion of elderly individuals exposed to these medications. In addition, chronic ASA for cardioprotection poses its own risks and further complicates strategies to reduce the GI risk imposed by NSAIDs.⁴

There are several strategies proven to reduce the risk of GI complications associated with NSAIDs.⁵ To choose an appropriate strategy, it is useful to consider relative GI risks in the context of other health concerns in the individual patient. While age over 65 is in and of itself an important risk factor for GI bleeding, this risk increases steeply in those with a history of peptic ulcer or particularly a history of prior upper GI bleeding.⁶ Anticoagulants such as warfarin increase bleeding risk, as does concomitant use of systemic corticosteroids, and antiplatelet agents such as ASA and/or clopidogrel. Helicobacter pylori infection also increases the risk of ulcers and ulcer bleeding in patients taking NSAIDs (Table 1). Each of these factors is at least additive, while some, such as H. pylori infection and NSAID use, are synergistic for ulcer and complications.⁷ For an elderly patient taking a NSAID, a high risk of GI complications can be conferred by any single additional risk factor, such as a history of bleeding, use of an anticoagulant or use of an antiplatelet agent. With the presence of two or more such risk factors, the relative risk is very high and more than one strategy for reducing bleeding risk may be appropriate.⁸

The most direct approach to risk reduction is avoiding NSAIDs altogether, but many patients with inflammatory joint diseases are unable to maintain an acceptable quality of life without chronic NSAID therapy. Alternatives to NSAIDs that provide adequate pain relief, such as narcotics, often introduce their own set of side effects that must be weighed carefully in the context of the patient’s risk of GI bleeding and their own criteria for an acceptable quality of life. In those patients maintained on NSAIDs, the two most common strategies are to offer a class of NSAIDs that are selective for COX-2, which pose a lower risk of GI complications than non-selective inhibitors of both COX-1 and COX-2, or to provide a gastroprotective agent. For optimal GI protection, the two strategies can be combined.⁹

When the roles of COX-1, which promotes cytoprotective prostaglandin synthesis, and COX-2, which predominantly mediates signalling for pain and inflammation, were differentiated, it was hoped that COX-2- selective NSAIDs would preserve the analgesia provided by the non-selective agents while eliminating GI risk. The initial enthusiasm about COX-2 selective inhibitors has been modified by two developments. The first was the appreciation that COX-2 selectivity is relative. Although COX-2 inhibitors typically produce less dyspepsia than non-selective NSAIDs, even those agents most selective for COX-2 are still associated with greater rates of dyspepsia and peptic ulcer than is observed with placebo.^10,11 Secondly, relative risk of CV events appears to be increased by available COX-2 inhibitors.¹² Although this risk is variable, it appears to be lower for those COX-2 inhibitors that have remained in the marketplace, and is shared by nonselective NSAIDs.¹³ Current NSAIDs carry regulatory warning labels about CV risk, a particular concern in an elderly population for whom the risk of CV events may exceed that of GI bleeding. Many questions about the mechanism(s) by which COX-2 selecti
NSAIDs increase the risk of CV events have been raised, particularly because there is little evidence to support a direct prothrombotic effect.

Table 1.

<img2925|center>

Gastroprotection with Proton Pump Inhibitors

Co-administration of gastroprotective agents is the most practical approach in the majority of patients whose risk for GI complications is considered moderate, such as those whose only risk factor is age over 65. The strategies best supported in controlled trials are misoprostol, a synthetic analog of prostaglandin E, and PPIs. However, misoprostol is not a comparable alternative to PPIs: cytoprotection requires a full dose at 200 µg four times per day and diarrhea develops in more than 20% of users. Furthermore, such protection against GI complications is modest.¹⁴

PPIs have demonstrated efficacy for healing NSAID-induced ulcers, and are more effective and better tolerated than misoprostol in controlled trials.¹⁵ The mechanism of action is suppression of acid, which is an important co-factor for the gastric mucosal damage induced by NSAIDs.¹⁶ The degree of acid suppression is important, as learned from controlled trials with H₂-receptor antagonists. While this drug class can be effective for healing NSAID-induced ulcers, omeprazole in a standard dose of 20 mg q.d. was more effective than 150 mg ranitidine b.i.d. for preventing recurrent NSAID-induced ulcers over six months.¹⁷ PPIs also have a high degree of safety and are well tolerated. However, one concern is that although PPIs show irreversible binding to the proton pump of the parietal cell which produces gastric acid, the onehour plasma half-life of these agents provides diminishing protection as new proton pumps are synthesized. This means that acid secretion is returning by the time that an evening dose of NSAID is taken. Most NSAIDs are acidic molecules and some, including naproxen, are administered on a b.i.d. basis. This disparity may be addressed by new strategies, such as combination pills that provide a PPI with the NSAID given twice daily.

Individual PPIs have not been compared for prophylaxis of NSAID-induced GI complications, although most are indicated for the treatment of NSAID-associated GI disease. The benefit of the PPI at the indicated dose results from the proportion of time with pH >4.0 over a 24-hour period. Two studies have suggested, at the doses studied, that esomeprazole is more effective for intragastric acid control than some other PPIs, including in patients taking NSAIDs.^18,19 The relevance of the greater anti-secretory effect of esomeprazole for preventing NSAID-induced ulcers has not been studied, but its efficacy in NSAID users includes significant benefit for preventing GI complications over H₂-receptor antagonists in patients continuing their NSAIDs.²⁰

The patients at highest risk of NSAIDinduced complications of the upper GI tract are generally those who have multiple risk factors. The most significant of these is a previous history of an upper GI bleed, but high doses of NSAIDs, concomitant use of multiple NSAIDs and simultaneous ASA, clopidogrel or anticoagulant therapy can elevate risk to a level where combining prophylactic strategies may be appropriate. In patients with a low to moderate risk of CV disease but a high risk of GI complications, the choice reasonably includes a combination of a COX-2 inhibitor and a PPI, which has been shown to be a viable strategy for risk reduction.²¹ Authors of several guidelines, including those written specifically for Canada, have suggested that this is a reasonable and prudent approach to the management of patients with multiple risk factors.^22,6 In patients at high risk of CV disease, strategies for reducing GI risk that avoid COX-2 inhibitors are preferable and the role of non-selective NSAIDs remains to be clarified in this situation.

Balancing Multiple Risk Factors

When the CV risks of COX-2 inhibitors were first recognized and subsequently confirmed to occur with non-selective NSAIDs, it was an important reminder of the potential risks of all therapies and it increased awareness of the inter-relationship of multiple organ systems. Moreover, this emphasizes the importance of a holistic approach to risk management, particularly in an elderly population. Earlier guidelines for managing the GI risk of NSAIDs attempted to define an acceptable balance between the inflammatory diseases and GI complications, and more recently have focused on considering multiple organ systems affected by NSAID use. For example, the risk posed by NSAIDs to the kidney leads now to evaluation of baseline renal function, while the potential role of NSAIDs for inhibiting the growth of cancers of the GI tract may be another important variable for future drug selection. In the lower GI tract, ASA provides established protection against cancer and this effect is also seen with COX-2 selective NSAIDs.²³ Both may be considered to reduce cancer risk in patients with familial adenomatous polyposis (FAP), but neither is recommended routinely as a treatment for cancer or as prophylaxis in patients without FAP.

It is clear that more sophisticated methodology for assessing relative risks and benefits of specific treatments are needed to improve clinical decision-making in the elderly who tend to have multiple comorbidities. There are accepted approaches for collating multiple risk factors for CV disease to provide a risk estimate over a specific interval of time, such as 10 years. However, the methodology for estimating multiple risks for GI events, such as an upper GI bleed, relies more on experience than science. It will be important to develop methodology to evaluate risks in different systems on the same scale for serious events, including fatal outcomes. Strategies to prevent NSAID-induced GI complications must be considered in the context of renal, CV and indeed overall health.

Summary

The risks posed by NSAIDs increase with age. While age alone is an important risk factor for NSAID-induced complications, including ulcers and life-threatening upper GI hemorrhage, older patients are also more likely to take anticoagulants and antiplatelet therapies, both of which increase the GI risks of NSAIDs. COX-2-selective NSAIDs, once considered to be an important part of the solution for managing GI risk, are now employed more discriminately because of their association with an increased risk of CV events. However, this CV risk is also seen with nonselective NSAIDs, which must also be taken into account in determining management strategies. While gastroprotection with PPIs is considered the most effective and safest approach to reducing the risk of GI complications, those at highest risk may be candidates for both a PPI and a COX-2 inhibitor depending on their relative CV risk. Based on differences between PPIs and H2-receptor antagonists, improved acid control is vital for upper GI protection.

References

1. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A metaanalysis. Ann Intern Med 1991;115:787-96.

2. Yeomans et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther 2005;22:795-801.

3. Kasman N, Bradley E. Arthritis-related prescription medications. In: Health Canada. Arthritis in Canada, an on-going challenge. Available from http://www. phac-aspc.gc.ca/publicat/ac/ac_9e-eng.php. Accessed Jan 5, 2009.

4. Sapoznikov et al. Minidose aspirin and gastrointestinal bleeding—a retrospective, case-control study in hospitalized patients. Dig Dis Sci 2005;50:1621-4.

5. Hunt et al. Approach to managing muscukolskeletal pain: acetaminophen, cyclooxygenase-2 inhibitors, or traditional NSAIDS? Can Fam Physician 2007;53:1177-84.

6. Tannenbaum et al. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol 2006;33:140-57.

7. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002;359:14-22.

8. Rostom A, Moayyedi P, Hunt R; Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009;29:481-96.

9. Targownik LE, Metge CJ, Leung S, Chateau DG. The relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. Gastroenterology 2008;134:937-44.

10. Bombardier et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-8.

11. Silverstein et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-55.

12. Ray et al. COX-2 selective non-steroidal antiinflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360:1071-80.

13. Lanas A, Hunt R. Prevention of anti-inflammatory druginduced gastrointestinal damage: benefits and risks of therapeutic strategies. Ann Med 2006;38:415-28.

14. Rostom et al. The prevention of chronic NSAID induced upper gastrointestinal toxicity: a Cochrane collaboration meta-analysis of randomized controlled trials. J Rheumatol 2000;27:2203-14.

15. Hawkey et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAIDinduced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998;338:727-34.

16. Plachetka et al. Integrated gastric acidity can predict the prevention of naproxen-induced gastroduodenal pathology in normal subjects. Gastroenterology 2003;124:A510.

17. Yeomans et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment. N Engl J Med 1998;338:719-26.

18. Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastrooesophageal reflux symptoms. Eur J Clin Pharmacol 2004;60:531-9.

19. Goldstein et al. Intragastric acid control in nonsteroidal anti-inflammatory drug users: comparison of esomeprazole, lansoprazole and pantoprazole. Aliment Pharmacol Ther 2006;23:1189-96.

20. Goldstein et al. Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAIDs: A randomized trial. Am J Gastroenterol 2005;100:2650-7.

21. Scheiman et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006;101:701-10.

22. Targownik LE, Thomson PA. Gastroprotective strategies among NSAID users; guidelines for appropriate use in chronic illness. Can Fam Physician 2006;52:1100-5.

23. Jankowski J, Hunt R. Counterpoint: cyclooxygenase-2 inhibitors in colorectal cancer prevention. Cancer Epidemiol Biomarkers Prev 2008;17:1858-61.

GENERIC PPIS: ARE THEY EQUIVALENT TO THE ORIGINAL FORMULATIONS?

Editorial Overview:

Peter J. Lin, MD

Director, Primary Care Initiatives, Canadian Heart Research Centre, Toronto, Ontario

The debate about whether generics are truly equivalent to the original formulations has always been controversial. Most recently with the genericization of proton pump inhibitors (PPIs), this debate may be fuelled by the fact that so many patients are taking this class of medication. Medications in general must show clinical benefit before they are approved. For example, in the case of PPIs, they had to show symptom relief, pH control or healing rates for esophagitis. The generic medications are judged differently. They are judged by bioequivalence and not clinical equivalence. This means that a generic has to have a blood level of plus or minus 20% of the original formulation. This is measured by the area under the curve (AUC). There is no need to show equivalence in symptom relief, pH control or healing rates. With so many patients depending on these medications, bioequivalence may not mean clinical equivalence, especially if the brackets are plus or minus 20%. Often patients are told that the generics are equivalent to the original formulation. For the legally minded, this would beg the question, who is responsible if there is a complication due to this difference in definition of equivalence? In the case of PPIs, what happens if there is bleeding or the development of a stricture?

Understanding Intervariability in Outcome

Bioequivalence, the basis for evaluating whether a generic drug can be substituted for a previously patented chemical compound, is based on plasma samples taken at regular intervals from healthy subjects who are tested in a crossover fashion. This can be a good definition if the acceptable range is very tight around the original formulation. Also, this could be very useful if a large enough sample size is taken to ensure that that tight range is maintained over the majority of the population. However, in reality, the number of subjects tested is often small, frequently fewer than 50 individuals. For PPIs, Health Canada deems a generic agent to be bioequivalent to the original formulation if the AUC does not differ by more than 20%.¹ Generics are not compared for the clinical outcomes for which the drugs are indicated, nor are they compared for relative safety. Although more rigorous standards are used for defining bioequivalence for compounds with a very narrow therapeutic window and substantial risk of toxicity, such as chemotherapies, this standard is not used when evaluating the PPIs.

PPIs heal lesions and control symptoms associated with acid-related diseases by inhibiting gastric acid secretion. There is a correlation between the degree of acid control and clinical benefit.² This correlation explains why PPIs are more effective than H₂-receptor antagonists, which in turn are superior to antacids for major outcomes.³ It also explains the significant difference among PPIs for healing of esophagitis.⁴ In large head-to-head studies using endoscopic evaluations, the PPI that offers the greatest 24-hour acid control, esomeprazole, had significantly greater healing of esophagitis relative to each of the other three PPIs to which it was compared (Figure 1).^5-7

Efficacy Considerations in Disease Severity

More interestingly, if you separate the patients out based on severity, there was an even more marked difference. In the patients with mild disease, all PPIs did well in terms of healing. But in the more severe cases, there was a clear advantage with esomeprazole. The reason for this might be the better pH control over 24 hours.⁸

The benefit seen is quite large. For example, in the study that compared once-daily doses of esomeprazole 40 mg to pantoprazole 40 mg, the patients with grade D (severe) esophagitis had healing rates that were 61.4% vs. 40.2%; P<0.001 at the end of four weeks in favour of esomeprazole. This is an absolute difference of almost 20% which translates to a number needed to treat (NNT) of only 5. A similar advantage for esomeprazole at increasing degrees of severity was also observed in head to head comparisons with omeprazole and lansoprazole.^5,6 In essence, there are differences even with the different forms of the original preparations of PPIs.

Bioequivalence vs. Clinical Equivalence

If within the different PPIs there is a difference in healing, then what would happen with generic therapies that could have up to 20% difference in drug levels? More importantly, without clinical data, one might not know the true effects of this potential variation. Also plasma drug levels are very useful for drugs that are active in the blood stream. However, PPIs remain inactive until they reach the highly acidic canuliculus of the acid-producing parietal cell.⁹ It is only there that they become activated. In other words, there are several steps after the medication reaches the blood before a PPI reaches its target and exerts its effects. These subsequent steps would not be captured in a simple AUC measurement. This would suggest that blood level bioequivalence may not be the same as clinical equivalence.

In one very small crossover study (N=7) that compared three generic formulations of omeprazole to the original formulation in seven patients,
not equivalent with the generics on the basis of 24-hour intragastric pH.¹⁰ Two of the generics were not superior to placebo for raising pH during night time hours.

Figure 1.

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The British Columbia Experience

The question that remains however, is that on a scientific basis, there might be a difference between generic and original formulations, but does this difference have any real impact on patients as a whole? In other words, do patients feel it or is this just a laboratory phenomenon? A natural experiment was carried out in British Columbia when all patients were put on a generic PPI. An analysis of the data from the generic PPI substitution program in British Columbia produced the conclusion that quality of life was diminished and the cost of care was increased due to the large number of patients whose symptoms returned when switched from the PPI they had been taking successfully to a low-cost alternative.¹¹ Of the 39,000 patients who filled a prescription for the low-cost PPI, during that time period, 9600 experienced treatment failure and had to obtain an exception to the policy to return to their previous PPI. The authors of the analysis concluded that the underlying assumption that PPIs are interchangeable was flawed. They further noted that cost analyses that included the expense of return office visits eliminated any potential cost savings.

Underlying Complications

There is one further complicating factor in the GERD treatment arena. Typically, if the medications are not the same, then stronger ones are used for the more severe cases. However, symptoms do not correlate with severity. This might be because the esophagus is a visceral organ so it does not have great innervation. Consequently, a lot of damage may not create many symptoms. This poor correlation between the presence or severity of symptoms and esophagitis happens even in its most severe forms, and this disparity increases with age. In one study of severe esophagitis patients, only 34% of patients had severe symptoms, and in fact a small proportion of these patients had no symptoms.¹²

One solution would be to do carry out an endoscopy on every patient to assess severity but this is not practical and is cost-prohibitive. Hence the majority of patients without alarm symptoms are treated empirically with PPIs. The generic entries may make this more complicated since bioequivalence based on blood levels may not translate into clinical benefit such as esophageal healing, for example.

Summary

The concept of equivalence is simple but its implemtation is difficult. Bioequivalence based on blood levels may not be the most appropriate. First, the range is large at plus or minus 20%. Second, only a small number of people are tested. Third, the PPIs are not active in the blood and several other steps are needed before they reach their target and become activated. None of these steps are captured based on blood levels. In other words, it would be difficult to conclude that a generic will have the same effects as the original formulation. In addition, there are differences in efficacy as measured by healing rates even within the original PPIs as shown with large head-to-head trials based on endoscopic examination. Hence the conclusion of the British Columbia researchers is correct that “the assumption that PPIs are interchangeable is flawed.” In the end, the goal is to protect the patient and in the case of GERD, this means the healing of the esophagus and the reduction of any future complications.

References

1. Health Canada. Bioequivalence Requirements: Comparative Bioavailability Studies Conducted in the Fed State. www.hc-sc.gc.ca/dhp-mps/prodpharma/ applic-demande/guide-ld/bio/fedstate_sujetsjeuneng. php. Accessed Jan 4, 2009.

2. Bell et al. Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 1992;51(suppl 1):59-67.

3. Armstrong et al. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults – update 2004. Can J Gastroenterol 2005;19:15-35.

4. Chiba et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta analysis. Gastroenterology 1997;112:1798-810.

5. Richter et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001;96:656-65.

6. Castell et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002;97:575-83.

7. Labenz et al. A randomised comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive esophagitis: the EXPO study. Aliment Pharmacol Ther 2005;21(6):739-46.

8. Miner et al. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003;98:2616-20.

9. Esplugues JV. A pharmacological approach to gastric acid inhibition. Drugs 2005;65(suppl 1):7-12.

10. Shimatani et al. Acid-suppressive effects of generic omeprazole: comparison of three brands of generic omeprazole with original omeprazole. Dig Liver Dis 2006;38:554-9.

11. Canadian Society of Intestinal Research. Stemming rising drug costs and providing quality patient care: a delicate balance. Executive Summary. Available at: www.badgut.com/index.php?contentFile=news022& title=Therapeutic Substitution – Why All Canadians Should be Concerned. Accessed Jan 2, 2009.

12. Johnson DA, Fennerty MB. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease. Gastroenterology 2004;126:660-4.