Update on the Management of Acid-Related Disorders: A Canadian Perspective

Transcription

1 A FREE CONTINUING EDUCATION LESSON OBJECTIVES This professional development activity shares the clinical experience of experts, demonstrates best clinical practices, and highlights new clinical trials pertaining to the management of GI acid-related disorders. At the completion of this activity, pharmacists should be able to: 1. recognize the clinical impact of acidrelated disorders and associated GI mucosal injury; 2. outline management strategies for patients with uninvestigated dyspepsia, GERD (erosive and non-erosive) and PUD; 3. identify candidates for GI prophylaxis in the setting of ASA/NSAID therapy; 4. discuss the role of the pharmacist in managing patients with, or at risk for, acid-related disorders. INSTRUCTIONS 1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. Circle the appropriate letter on the attached reply card. 2. Complete the card and mail, or fax to (416) Your reply card will be marked and you will be advised of your results within six to eight weeks in a letter from Rogers Publishing. 4. To pass this lesson, a grade of 70% (14 out of 20) is required. If you pass, your CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces require individual pharmacists to notify them.) THIS FREE LESSON IS APPROVED FOR 1.5 CE UNITS Approved for 1.5 CE units by the Canadian Council on Continuing Education in Pharmacy. File # Update on the Management of Acid-Related Disorders: A Canadian Perspective By Doret Cheng, BScPharm, PharmD and Lisa Burry, BScPharm, PharmD, FCCP Doret Cheng is an internal medicine clinical pharmacy specialist with an active clinical and research practice at Mount Sinai Hospital in Toronto. Doret is the Medicine Clinical Coordinator at Mount Sinai where she deals with patients with dyspepsia as well as those with GI bleeding and other ulcer complications. Doret is currently leading a working group on an initiative to improve GI acid suppressive practices at Mount Sinai Hospital. She is a tutor for the Faculty of Pharmacy at the University of Toronto. Lisa Burry is a critical care clinical pharmacy specialist with an active clinical and research practice in the Medical-Surgical Intensive Care Unit at Mount Sinai Hospital in Toronto She is also the Surgical Clinical Coordinator for Mount Sinai Hospital. Lisa deals with patients with active GI bleeding as well as those at high risk of other GI ulcer complications. Lisa has provided many presentations to pharmacists and physicians on the management of variceal and non-variceal GI bleeding and is currently working with Doret Cheng on an initiative to improve GI acid suppressive practices at Mount Sinai Hospital. She is a tutor for the Faculty of Pharmacy at the University of Toronto. The authors, reviewers and Pharmacy Practice magazine have each declared that there is no real or potential conflict of interest with the sponsor of this lesson. INTRODUCTION Dyspepsia is the main manifestation of acid-related conditions: functional or non-ulcer dyspepsia (FD/NUD), gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD) and gastric, esophageal or pancreatic cancer. The prevalence of dyspepsia in Canada has been estimated at approximately 29% and may be as high as 50% in Western countries. 1 It significantly decreases health-related quality of life and in Canada, over $670 million is spent on medication alone. 2,3 Dyspepsia is a symptom complex rather than a disease and its definition has evolved over the last decade. It is difficult to establish a unifying definition of dyspepsia since subjective symptoms and their interpretation vary between patients, physicians and even culture and language. The Canadian Dyspepsia (CanDys) Working Group defines dyspepsia as a symptom complex of epigastric pain or discomfort thought to originate in the upper gastrointestinal tract, and [which] may include any of the following symptoms: heartburn, acid regurgitation, excessive burping and/or belching, increased abdominal bloating, nausea, feeling of abnormal or slow digestion or early satiety. 1 The majority of patients with symptoms of upper gastrointestinal (GI) discomfort will present to the community pharmacy or family physician seeking SUPPORTED BY AN EDUCATIONAL GRANT FROM March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 1

2 advice and/or a diagnosis. It is therefore crucial that pharmacists recognize the typical signs and symptoms and more importantly the alarm features for appropriate recommendations and referral. Pharmacists are in a prime position to identify patients who have an acidrelated gastrointestinal disorder, to assess their level of risk for complications, to educate patients on self-management, and to optimize care through collaboration with patients and physicians. DETECTION & MANAGEMENT OF GASTROINTESTINAL ACID-RELATED DISORDERS A) Uninvestigated dyspepsia Prior to investigational work-up, patients with dyspeptic symptoms are considered to have uninvestigated dyspepsia. The CanDys Working Group, consisting of a multidisciplinary group of specialists, family physicians and pharmacists, developed a clinical management tool (CMT) based on best available evidence and expert opinion for patients who present with new-onset or recurrent dyspepsia. 1 This tool provides the primary-care physician with five key questions to stratify and manage patients based on clinical features and symptoms (Fig 1). A unique feature of this tool is that it highlights and prompts the physician to address the importance of possible non-gi causes of dyspeptic symptoms, which will require further investigation. The alarm symptoms requiring urgent investigation include vomiting, evidence of gastrointestinal blood loss or anemia, abdominal mass or involuntary weight loss, dysphagia, odynophagia and chest pain. 3 These symptoms may be suggestive of an organic cause and pharmacists should advise patients to contact their physicians immediately for further investigation. B) GERD Gastroesophageal reflux disease (GERD) is defined as reflux of gastric contents into the esophagus causing symptoms sufficient to reduce quality of life and/or esophageal injury. 3 It is the most common gastrointestinal and acid-related disorder in Canada. In a survey of over 1,000 Canadians, 17% reported heartburn in the preceding three months and FIGURE 1: Treat as Hp negative NO Uninvestigated dyspepsia NO Other possible causes? NO Age >50 or alarm features? Vomiting Bleeding/anemia Abdominal mass/ unexplained weight loss Dysphagia NO NSAID and/or regular ASA use? NO Is dominant symptom heartburn or regurgitation? NO Hp test positive? 1. UBT 2. Serology 13% had moderate to severe symptoms on a weekly basis. 4 Quality of life is significantly affected, with patients reporting a poorer quality of life than those with diabetes, hypertension, mild heart failure or arthritis. 5 The typical presentation of GERD includes heartburn and regurgitation. Heartburn may wax and wane, and is usually worsened by lying down and ingestion of food. In a recent Canadian study (CADET-PE), reflux esophagitis was by far the most common endoscopic finding in patients with uninvestigated dyspepsia regardless of the dominant symptom reported. 6 Most patients with typical GERD symptoms do not undergo investigation; therefore the term Consider Cardiac Hepatobiliary Medication-induced Dietary indiscretion Other Treat as appropriate Investigate (Endoscopy recommended) Treat as NSAID-induced (See section on peptic ulcer disease) Treat as GERD (see section on GERD) Treat as Hp positive Adapted from the CanDys Clinical Management Tool. 1 ASA=Acetylsalicylic acid; Hp=Helicobacter pylori; NSAID=Nonsteroidal anti-inflammatory drug; GERD=Gastroesophageal reflux disease; UBT= Urea breath test YES YES YES YES YES heartburn-dominant uninvestigated dyspepsia encompasses GERD. 3 Reflux disease can also produce atypical symptoms (extraesophageal manifestations) such as shortness of breath and wheezing, cough, pharyngitis, hoarseness, and chest pain (see Table 1). Symptoms of acid reflux are likely due to poor gastric emptying and contact of esophageal mucosa with acid and pepsin. Structural and physiological mechanisms such as the lower esophageal sphincter (LES), bicarbonate in saliva, and esophageal peristalsis form the body s anatomic defence against reflux. LES dysfunction due to transient relaxations and decreased tone, esophageal peristaltic dysfunction and abnormal gastric emptying may play a role in the development of GERD. A number of factors may alter natural defence mechanisms and increase the risk of reflux: Lifestyle factors (e.g. smoking, large 2 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

3 TABLE 1: Extraesophageal manifestations of GERD ENT Cough Globus (sensation of lump in the throat) Hoarseness/voice changes Laryngeal cancer Laryngitis Otitis media Pharyngitis Sinusitis Subglottic stenosis Vocal cord granulomas Pulmonary Asthma Cough Chronic bronchitis Idiopathic pulmonary fibrosis Pneumonia Miscellaneous Chest pain Dental erosions Sleep apnea Source: Fennerty MB. Extraesophageal gastroesophageal reflux disease. Gastroenterol Clin North Am 1999; 28: TABLE 2: Medications that may worsen GERD Drugs that LES pressure Anticholinergic agents Barbiturates Benzodiazepines Caffeine and derivatives (aminophylline, theophylline) Dihydropyridine calcium channel blockers Estrogen Ethanol Narcotics (meperidine, morphine) Nicotine (smoking) Nitrates Progesterone Drugs that irritate the esophageal mucosa ASA Bisphosphonates Iron Non-steroidal anti-inflammatory drugs Potassium chloride Quinidine Source: Weinberg DS, Kadish SL. The diagnosis and management of gastroesophageal reflux disease. Med Clin North Am 1996; 80: meals, fatty foods, caffeine, pregnancy, obesity, body position and estrogen) Medications that lower LES pressure or cause direct GI irritation (Table 2) Hiatus hernia (increased esophageal exposure to gastric contents) The severity of symptoms and degree of mucosal damage correlates with duration of exposure of the esophagus to gastric acid (duration of time ph<4). 3 Therapies that prolong gastric acid suppression are therefore desirable for faster symptom relief and improved healing rates. Lifestyle modification appears to have limited effectiveness for patients with severe and frequent GERD and welldesigned controlled trials are needed to make any definitive conclusions regarding clinical efficacy. 7 Despite the sparseness of controlled data, clinical experience suggests that patients with mild symptoms would likely benefit from strategies such as elevating the head of the bed, avoiding lying down within two hours of eating, avoiding food and medication triggers, reducing weight, quitting smoking, and decreasing coffee and alcohol consumption. 3,7 Various comparative trials have shown that over-the-counter antacids alone or combined with low-dose histamine-2 receptor antagonists (H 2 RAs; e.g. ranitidine 75 mg or famotidine 10 mg) and antireflux agents such as alginic acid and are effective for symptom relief in mild GERD. 3,7,8 There is suggestion that antacids provide quick relief and OTC H 2 RAs provide a longer duration of relief. 9 There are very few well-designed studies comparing OTC H 2 RAs and antacids; however, due to the availability and safety profile of these agents, they are reasonable alternatives for patients with very mild and infrequent symptoms, particularly if symptoms are associated with meals or triggered by certain foods. 3 Prokinetic or promotility agents such as cisapride, metoclopramide and domperidone have been studied in the treatment of GERD. These agents have been proposed to peristalsis and LES tone. Cisapride is the only prokinetic agent that has shown clinical efficacy 10 ; however, it is no longer available on the market in Canada and is now only available through the special access program due to concerns about prolongation of QT interval, ventricular tachycardia and death. Due to the paucity of clinically relevant data, these agents are not recommended alone or in combination with anti-secretory agents for the long-term maintenance treatment of GERD. 3,11 The 2004 Canadian GERD Consensus guidelines recommend that a once-daily proton pump inhibitor (PPI) should be used for the empirical treatment of GERD unless symptoms are mild and infrequent (i.e. fewer than three times per week). 3 This recommendation is supported by a meta-analysis of 13 trials in more than 3,000 patients where PPIs were approximately twice as effective as H 2 RAs. 12 Furthermore, 2 recent Canadian studies showed that PPIs provide the highest rate of relief during the first 2-4 weeks of therapy compared to H 2 RAs. 13,14 The CADET Heartburn-Dominant (CADET-HR) study 13 compared heartburn relief in patients with uninvestigated dyspepsia with PPI or an H 2 RA. Three-hundred and ninety patients were randomized to either omeprazole 20 mg daily or ranitidine 150 mg twice daily for the first 4-8 weeks, with an escalation in therapy to omeprazole 40 or 20 mg, respectively if symptoms persisted. Results indicated that a PPI provides better symptom relief at 4 weeks, but no difference was observed for subsequent relapses during a 6-month treatmentfree follow-up period. Forty-seven percent (47%) of patients on ranitidine required escalation therapy due to inadequate heartburn relief, compared to 26% of patients who had started with omeprazole. At 4 weeks, the difference in heartburn relief was 27.8% in favour of PPI-start strategy (55.1% vs. 27.3%, p<0.001). The difference in median times to sustained heartburn resolution was 24 days in favour of PPI (5 vs. 29 days), and at 4 weeks the PPI-start strategy was better in achieving additional heartburn relief and sustained effect (NNT = 4). The multi-centre CADET-HN study 14 comparing omeprazole, ranitidine, cisapride, or placebo in H pylorinegative primary-care patients with dyspepsia was recently published, providing March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 3

4 more evidence that PPIs provide better symptom relief compared to H 2 RAs and motility agents. Five-hundred and twelve patients were randomized to 4 weeks of treatment with omeprazole 20 mg daily, ranitidine 150 mg twice daily, cisapride 20 mg twice daily or placebo followed by on-demand therapy for an additional 5 months. The study s primary outcome measure was the Global Overall Severity (GOS) score at 4 weeks, measuring dyspepsia symptoms. At baseline, included patients reported at least moderate symptom severity (GOS at least 4/7). A score of 1 or 2 defined treatment success. Treatment success at 4 weeks was omeprazole 51.1%, ranitidine 36%, cisapride 30.5% and placebo 23.3% (NNT = 4, omeprazole vs. placebo; NNT = 7, omeprazole vs. ranitidine). At 6 months there were no statistically significant differences between groups in terms of symptom relief. Evidence of erosive esophagitis (EE) on endoscopy accounts for up to twothirds of patients with symptoms of reflux or 5 to 12% of the general population. 3 The presence and severity of EE does not correlate with the severity of symptoms, however there is a correlation with complications such as esophageal strictures and Barrett s esophagus (BE). Severity of EE has been graded using the LA classification system (see Table 3) based on endoscopic evidence. Multiple studies and meta-analyses provide evidence that PPIs in acute and long-term treatment provide significantly greater symptom relief and healing compared to H 2 RAs or cisapride in EE (absolute differences in healing rates of 30-40%). 15 In addition, standard dose PPIs (Table 4) are more effective than low-dose PPIs. 16 Standard dose PPIs (Table 4) have been compared in 24-hour intragastric ph studies. According to a 5-way crossover trial comparing esomeprazole 40 mg to all other agents at standard doses, esomeprazole provided a longer duration of acid suppression (ph>4). 17 At this point, no unifying recommendations have been made regarding choosing one PPI over another since the clinical relevance of various direct comparisons is still under debate. 3,18 Barrett s esophagus (BE), a metaplastic change from normal esophageal squa- TABLE 3: The Los Angeles classification system for the endoscopic assessment of esophagitis Grade A B C D TABLE 4: Standard daily doses of proton pump inhibitors and H 2 RAs 1,3 Rx Daily Dose Management of GERD/Heartburn Proton Pump Inhibitors Esomeprazole 40 mg 4 weeks* then reassess; if inadequate Lansoprazole 30 mg response, increase to twice-daily dosing Omeprazole 20 mg (4-8 weeks) + Pantoprazole 40 mg Rabeprazole 20 mg Histamine-2 Receptor Antagonists Cimetidine 400 mg OD or BID 4 weeks* then reassess; if inadequate Famotidine 20 mg OD or BID response, change to PPI (4-8 weeks) + Nizatidine 150 mg OD or BID Ranitidine 150 mg OD or BID *Stop therapy after 4 weeks if symptoms resolved. If symptoms recur, repeat original therapy. Pts with EE or BE should be on continuous maintenance therapy. +If no response after 4-8 weeks of intensified therapy, further investigation is warranted. TABLE 5: H pylori diagnostic testing Method Endoscopy not required Urea Breath Test (UBT) Blood Fecal antigen Endoscopy required Rapid Urease tests Histology Culture Definition One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the mucosal folds. One or more mucosal breaks more than 5 mm long; none of which extends between the tops of 2 mucosal folds. Mucosal breaks that extend between the tops of 2 or more mucosal folds, but which involve less than 75% of the esophageal circumference. Mucosal breaks which involve at least 75% of the esophageal circumference. Source: Lundell L, Dent J, Bennett J, et al. Endoscopic assessment of oesophagitis: Clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45: Adapted from 33,39 Comments UBT detects active infection by testing for the enzymatic activity of bacterial ureases. Antibodies can be detected from blood, plasma or serum. Serology will remain positive for those previously infected as antibodies remain after eradication. Fecal antigen testing identifies active infection by detecting the presence of antigens in stools. Endoscopy is highly sensitive for the diagnosis of GU/DU and allows for biopsies and cytologic brushings in order to differentiate a benign ulcer from a malignant lesion Culture primarily used in research studies Much more invasive and expensive compared to UBT, blood and fecal antigen testing 4 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

5 mous epithelium to columnar intestinal epithelium, is a serious complication of GERD. The incidence of BE increases with higher frequency (>3 times per week), severity and duration (>20 years) of GERD symptoms. BE has been associated with the development of esophageal adenocarcinoma; Canadian data show that the absolute risk of progression to adenocarcinoma in patients with long-standing GERD is approximately 0.4%. 19 Although the likelihood of gastric or esophageal cancer is relatively low, the prevalence of cancer increases with age (>50) and with the severity, frequency and duration of GERD symptoms. North American gastroenterology guidelines recommend lifelong PPI therapy for BE patients along with periodic endoscopic surveillance. 19,20 A strategy called once in a lifetime endoscopy has been developed for patients with chronic GERD, calling for endoscopy after 10 years of GERD symptoms to identify patients who have BE. Notwithstanding, life-long PPI treatment and once in a lifetime endoscopy has not been shown to reduce the incidence of gastric or esophageal cancer. 19 For patients who fail to respond to standard-dose therapy and/or with severe esophagitis (LA Grade C or D, or stricture), some may obtain relief with double-dose or longer duration of PPI therapy. 21,22 Recently, there have been some data to suggest that high-dose PPI therapy reduces symptoms in patients with extraesophageal manifestations of GERD such as non-cardiac chest pain (NCCP). Two meta-analyses showed that using higher doses of PPI (omeprazole 40/80 mg or lansoprazole 30 mg) for up to 4 weeks is a useful and potentially cost-saving strategy to diagnose and treat patients with NCCP. The small number of trials and patients included in these meta-analyses limit their generalizability; therefore more evidence is needed to confirm these results. 23,24 C) Functional (non-ulcer) dyspepsia The diagnosis of functional dyspepsia (FD), also referred to as non-ulcer dyspepsia (NUD) is defined as 12 weeks or more of persistent or recurrent dyspepsia within the last 12 months plus the absence of evidence that organic disease is likely to explain the symptoms (including evidence from upper endoscopy). 2 This implies that a complete diagnostic evaluation has been completed and any obvious structural abnormality such as PUD or reflux esophagitis has been ruled out. Symptoms are frequently described as ulcer-like (e.g. burning) or dysmotilitylike (e.g. nausea, bloating, early satiety, anorexia). Several pathophysiologic mechanisms have been proposed: motility abnormalities, visceral sensory abnormalities, psychological factors or chronic gastritis secondary to infection. One of the more prevalent theories currently being investigated is the possible relation between Hp infection and FD/NUD. Dyspepsia has been shown to occur after intentional Hp infection, 25 suggesting a correlation; however, treatment results have been inconsistent and the role of Hp in non-ulcer dyspepsia remains controversial Psychosocial factors (e.g. anxiety, depression and stress) have been shown in epidemiological studies to be more prevalent in patients with FD/NUD. A systematic review evaluated the effects of psychotherapy, cognitive behaviour therapy, relaxation therapy and guided imagery or hypnosis. 30 The 3 trials included in the review showed improvement of symptoms at 12 weeks; however, the effect was no different after one year. Due to the heterogeneity of these studies, the results were not pooled and no specific recommendations were derived. Psychotherapy should be evaluated on an individual basis and considered in patients with a significant psychiatric condition or as an adjunct to medical management. The management of FD/NUD is often based on the predominant symptoms patients report. A plethora of data has been published and recently a Cochrane review analyzed 61 pharmacological intervention trials (antacids, bismuth salts, sucralfate, misoprostol, prokinetic agents, H 2 RAs and PPIs) for NUD. 31 Due to trial limitations and significant heterogeneity, the management of NUD remains challenging and subjective. Nevertheless, indirect comparisons of the trials suggest that choice of therapy should be based on individual dyspepsia symptoms. Prokinetic agents were significantly better than H 2 RAs for symptoms of dysmotility such as nausea and early satiety, whereas H 2 RAs were better for heartburn. The evidence for antisecretory agents for reflux symptoms is strongest for PPIs as the studies were generally of higher methodological quality. However, due to the significant overlap in patients with symptoms of GERD and NUD, management of these patients mirrors that of GERD. More evidence is needed with clear delineation of patients and symptoms before any conclusions can be made. 31 D) Peptic ulcer disease (PUD) A peptic ulcer is a non-malignant lesion in the GI mucosa that may be acute, subacute or chronic. The major forms are duodenal ulcer (DU) and gastric ulcer (GU), and it is not uncommon for patients to develop both simultaneously. Lifetime prevalence is estimated to be 4-10% and is significantly higher in Hppositive subjects % In general, a poor correlation exists between dyspeptic symptoms and presence of ulcers and there is no symptom complex that can adequately differentiate between GU, DU and NUD. 33,34,36 Patients may experience minimal symptoms while others have severe initial presentation. Classic symptoms have been described as epigastric pain between the xiphoid process and the umbilicus or discomfort characterized by fullness, bloating, distention or nausea. 35,36 Potential complications include hemorrhage (15-20%), perforation (5%), and gastric outlet obstruction (2%). 36 Two decades ago, almost all peptic ulcers were considered to be idiopathic or due to excess gastric acid, stress or diet. Although acid injury is necessary for ulcers to form, acid secretion is normal in almost all patients with GUs and increased in only one-third of patients with DUs. Today, it is well known that PUD is the end result of a number of etiological factors that disrupt GI defence. H pylori infection and NSAIDs are now widely accepted as the major contributors to this disequilibrium. 33,34 The remainder of this discussion attempts to update the reader on new guidelines or March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 5

6 clinical trials related to Hp, NSAIDs and the relationship between the two. TABLE 6: Regimens for H pylori eradication Regimen Comments Triple Therapy PPI bid Duration 7-14 days + Eradication rates of 80-90% in RCTs clarithromycin 500 mg bid Clarithromycin 250 mg bid may be used in + metronidazole-based regimens but is inadequate {amoxicillin 1 g bid if combined with amoxicillin or metronidazole 500 mg bid} Metronidazole is typically substituted for amoxicillin for penicillin allergic patients Quadruple Therapy H 2 RA bid or PPI bid Ranitidine bismuth citrate was discontinued + from the Canadian market in Bismuth subsalicylate Ranitidine should not be substituted for ranitidine (525 mg) ii tab qid bismuth citrate + Duration 14 days metronidazole 250 mg qid Eradication rates of 75-85% in RCTs or 500 mg tid + tetracycline 250 mg qid or 500 mg tid TABLE 7: Risk Factors for NSAID/ASA-Induced Ulcers and Upper GI Complications Established Advanced age (>65 years) History of PUD or ulcer-related complication (e.g. upper GI bleeding) High-dose NSAIDs ASA (including low cardioprotective dosages) Coagulopathy or concomitant anticoagulant or antiplatelet Rx - markedly increase the risk of bleeding when used concurrently with NSAIDs or ASA. There is evidence to suggest that antiplatelet drugs such as clopidogrel and ticlopidine also increase the risk of GI bleeding when used in combination with NSAIDs or ASA. Concomitant illness (e.g., cardiovascular disease, rheumatoid arthritis) Concomitant use of corticosteroids Possible NSAID-related dyspepsia Duration of NSAID use (however as little as one week exposure has been reported) Adapted from 33,52,56-59 i) H pylori H pylori infects ~20% of the western world s population; the incidence and prevalence varying with age and economic status. 37,38 Factors associated with an increased prevalence include low socio-economic status, poor sanitary conditions and overcrowding. Up to 20% of those infected with Hp are found to have PUD, with >90% identification in DUs and 70-85% in GUs. 33,39 Curing Hp infection will not only reduce the ulcer recurrence rate but also the risk of type-b chronic atrophic gastritis, peptic ulcer dyspepsia, and low-grade gastric MALT lymphoma H pylori can be detected using either invasive or non-invasive techniques (see Table 5). Important considerations in selecting a test are availability, accuracy, prior treatment for Hp, cost-effectiveness, the appropriateness of endoscopy, and clinical circumstances that may affect the results. 39,42 As the incidence and prevalence of Hp seems to be decreasing in industrialized nations, including Canada, the role of accurate testing becomes increasingly important and primary care diagnostic tests that were once adequate need reappraisal. 42 The 2004 Canadian H pylori Study Group (CHSG) Consensus does not recommend stool antigen tests as an acceptable tool to diagnose infection in community-based practice based on lack of sufficient evidence and the need for dedicated and experienced laboratory staff. 42 Serology was not considered to be accurate in many Canadian populations because, as the prevalence of infection declines, the predictive value of serology will become less reliable. 42,43 For now, the urea breath test remains first choice when endoscopy is not indicated. Since Hp was first cultured from the human GI tract in 1984, the relationship between it and GI ulcers has been explored in >3,000 RCTs, with a multitude of data supporting eradication rates of up to 96% with some regimens. 33 Compared with acid suppression alone, Hp eradication therapy has been well proven to facilitate ulcer healing and reduce ulcer recurrence and complication rates several-fold. 33,42 After successful eradication of Hp, recurrences of PUD are expected to be <5% annually. 33,44 Given the proven importance of eradicating infection, finding the ideal regimen is vital. Single- and dual-agent therapy should not be used because of the unacceptably low eradication rates (<70%). CHSG guidelines suggests quadruple therapy for days is as effective and well tolerated as 7-10 day PPI-based triple therapy regimens (see Table 6). 42,45,46 However, given the complexity of a quadruple regimen, triple therapy with a PPI is often made first choice in practice. Newer evidence is emerging to suggest PPI-based triple regimens are more effective if administered for 14 days, although the increase in benefits is small (~5%). 42,47 Treatment of Hp infection is now complicated by a growing phenomenon of antibiotic resistance, which will negatively impact eradication rates and limit the utility of some of the current options. 42 Pre-treatment antimicrobial resistance also has an important negative impact on the efficacy of many regimens. A recent study from Nova Scotia reported the following pretreatment resistance rates: clarithromycin, 11%; metronidazole, 19%; tetracycline, 2%; 6 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

7 TABLE 8: Strategies for Reducing GI Risk in Patients Receiving Chronic NSAID Therapy Risk Definition Suggested management Low <65 yr, no ASA, no prior ulcer or Non-selective NSAID alone GI complication Moderate One to two risk factors Partially selective NSAID (e.g. meloxicam) (e.g., age >65 yr, high-dose plus PPI or misoprostol; or selective COX-2 NSAIDs, low-dose ASA) inhibitor High 3 risk factors or concomitant ASA, Selective COX-2 inhibitor plus PPI or corticosteroids or warfarin misoprostol* Very high Prior ulcer or ulcer-related Selective COX-2 inhibitor plus PPI or complication misoprostol* Consider avoiding non-selective NSAIDs and selective COX-2 inhibitors *Not studied in prospective RCTs; theoretically useful. Levels of risk represent general, but not complete agreement among experts. The preferred strategy for each group remains uncertain and some of the suggested strategies have not been investigated in appropriate clinical trials. Compiled from references 56,57,60-62,73-75 and amoxicillin, 0%; confirming published U.S. data. 42,48,49 Cases in which the patient has undergone more than one treatment without successful eradication of Hp infection are typically difficult to manage with low likelihood of cure. CHSG suggests susceptibility testing for those who fail first-line therapy to guide selection of the second treatment regimen. 42 Traditionally, second-line treatments have been quadruple agent regimens. Recently, second-line therapy with a fluoroquinolone-based triple regimen (e.g. levofloxacin 250 mg bid + amoxicillin 1 g bid + esomeprazole 40 mg bid for 10 days) has been explored. 50,51 Preliminary results with fluoroquinolones are promising as eradication rates >80% have been reported but results are still preliminary and so the use should be reserved for those who have failed firstline treatments. ii) NSAID-related PUD NSAIDs are the second most common cause of PUD and ulcer-related upper GI complications The most significant NSAID-associated gastrointestinal toxicities are peptic ulcers (~40% of chronic users have endoscopic ulcers) and serious complications (~1.5%) such as upper GI bleeding and perforations, that result in significant morbidity and mortality. 42 Given the widespread use and the incidence of serious GI complications with NSAID (~3%/year), an exposure of 10 million patients could result in 300,000 potentially fatal complications annually. 33,52,56 Risk factors for ulcers and complications secondary to NSAIDs are presented in Table 7. Additive risk is conferred when risk factors are combined. 57 Prevention should be considered for those at increased risk for GI injury or those who would be at significant risk for morbidity/mortality if a complication developed. A number of strategies have been used to reduce the risk of NSAID-related ulcers and complications: buffering or enteric coating of the NSAID formulation; antacids; sucralfate; H 2 RAs; misoprostol; PPIs (see Table 8). There is insufficient evidence to support the use of buffer or enteric coating, antacids or sucralfate in reducing the risk of NSAID-related ulcers and their complications. H 2 RA co-therapy has been shown to be effective in reducing the risk of endcoscopic duodenal but not gastric ulcers. Double-dose H 2 RA co-therapy was effective at reducing the risk of endoscopic DU and GU. 52,53,55-57,60,61 Misoprostol has been shown to reduce the risk of ulcer 56-58,60-62 and serious ulcerrelated GI complications. 57,62 Misoprostol 800 mcg/day was superior to 400 mcg/day for the prevention of endoscopic gastric ulcers; a dose response relationship was not seen with duodenal ulcers. 52,53,56,61 However, multiple daily dosing, its uterotrophic effects, abdominal cramping, and dose-related diarrhea limit its use. The total daily misoprostol dosage may be reduced to minimize diarrhea, but dosages as low as 400 mcg/day may compromise its gastroprotective effect. Substantial data has proven concomitant use of a PPI substantially reduces the risk of DU and GU associated with non-selective NSAIDs compared to various other therapies 56,57,60,61,64-66 Overall, H 2 RAs and PPIs are better tolerated than misoprostol, and reduced NSAID related dyspeptic symptoms. 61 An alternative proposed approach has been to use COX-2 selective NSAIDs, as it was previously observed that NSAIDs with greater inhibition of COX-2 versus COX-1 appeared to be associated with a lower prevalence of GI ulceration and erosions on endoscopic evaluation. 57,67-69 This review would not be complete without a brief discussion of the recent COX-2 trials, despite the fact that in late 2004, evidence became available associating COX-2 use with significant cardiovascular concerns, increased risk of heart attach and stroke, compared with placebo. Since the publication of this information celecoxib is the only remaining selective COX-2 agent on the Canadian market and is typically avoided in those at risk of cardiovascular events. Two large multicentre, double-blind trials, CLASS 67 and VIGOR, 68 examined the GI safety of COX-2 agents. Both trials used high doses of the specific COX-2 inhibitor and selected patients in the CLASS trial received low-dose ASA. Initial analysis of the CLASS and VIGOR trials indicated that both celecoxib and rofecoxib decreased the risk of developing upper GI clinical events and complications by ~50% when compared with traditional agents in patients not taking concomitant low-dose ASA. The beneficial effects of a COX-2 inhibitor may abolish the GI safety of these agents as suggested in the CLASS study posthoc analyses. 67 The utility of PPIs in combination with non-selective NSAID versus COX-2 selective inhibitors have been explored as a means to reduce the risk of recurrent bleeding in Hp-negative patients with a recent history of ulcerrelated bleeding. 70 Results suggest that using celecoxib monotherapy is as effective as adding a PPI to a non-selective NSAID among patients with a recent March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 7

8 TABLE 9: Strategies for approaching Hp status in the setting of NSAID Therapy history of ulcer bleeding. 70,71 There is growing clinical use of combined COX- 2 inhibitors with acid suppressive therapy or misoprostol, especially in those with very high risk of complications or previous history of PUD events. Although such combination may offer theoretically better GI protection, especially in very high risk circumstances, to date, there are no published outcome trials to establish the benefits of these combinations. 61,73 When an active ulcer is suspected or confirmed, therapy with the NSAID should be stopped whenever possible and smoking should be stopped to improve healing. 33,42,52,53 PPIs are the preferred treatment as they provide a rapid rate of ulcer healing, especially in the setting of complicated, large ulcers. 32,39,42,52 If chronic NSAID therapy must be continued potential options include use of a COX-2 selective NSAID (e.g. celecoxib), reducing the dosage of the nonselective agent and/or adding concomitant therapy with PPIs or misoprostol. 33,52,60 PPIs are the drugs of choice when the NSAID must be continued, as potent acid suppression is required to accelerate ulcer healing. 52,53,56 iii) H pylori interaction with ASA/NSAIDs An interaction between Hp and NSAIDs is biologically plausible given their different mechanisms of disrupting gastric mucosal defense but published data did not always confirm this. 62,76-86 A recent H pylori Test-&-Treat Approach Long-Term PPI Therapy Naïve to ASA/NSAIDs a) Naïve ASA users b) Naïve NSAIDs users with evidence Chronic ASA users a) With a recent ulcer complication with evidence with evidence b) At high risk for ulcer complication c) At low risk for ulcer complication Chronic NSAIDs users a) With a recent ulcer complication Potential benefit with evidence b) At high risk for ulcer complication Potential benefit c) At low risk for ulcer complication Adapted from 56,70,83-89 systemic review demonstrated synergism between Hp and NSAIDs for the development of PUD and ulcer bleeding. 87 The risk of PUD was reported to be ~60-fold higher in Hp positive NSAID users compared with Hp-negative subjects not taking NSAID. Moreover, Hp infection was shown to increase the risk of ulcer bleeding by 1.8-fold, NSAID use by 4.85-fold, and the presence of both factors by 6.1-fold compared with the risk of bleeding among Hp-negative subjects not taking NSAID. Table 9 summarizes the published data in this area and current clinical practice. 56,70,86,88,89 CHSG supports Hp testing and eradication for naïve NSAID users. 42,86 A similar strategy has also been suggested for naïve ASA users, although the efficacy of such an approach has not been confirmed. In chronic ASA/NSAIDs users, recommendations depend on the risk of PUD complications 56 and the type of NSAID. Based on published data, it is reasonable that any attempt to eradicate Hp infection should follow ulcer healing in the management of chronic NSAID users, although the efficacy of such an approach remains to be confirmed. 84,88 The efficacy of Hp eradication in chronic ASA users without a history of PUD complications has not been evaluated. ROLE OF THE PHARMACIST The management of GI acid-related disorders continues to evolve with a wealth of literature for both functional and organic acid-associated conditions. As pharmacists are often the first healthcare professionals encountered by the patient, we are uniquely positioned to identify, counsel and monitor patients requiring acute or chronic therapy for conditions related to gastric acid. Pharmacists should have a working knowledge of the pathophysiology of gastric acid-related diseases, risk stratification, potential under- and over-treated acid-disorders, as well as the efficacy and safety of the available pharmacological agents/regimens. The patient interview should include a patient s past medical and medication history, the nature and timing of symptoms and the presence of alarm features. Intervention through education, counselling and recommendation of initial non-prescription therapies such as antacids or H 2 RAs may be appropriate for patients at low risk. Collaboration with physicians is vital when pharmacists identify and refer patients with alarm symptoms. The patient should be educated regarding the disease state and its potential consequences. Through medication reviews, pharmacists can identify: Medications that are ulcerogenic or promote injury to the esophageal and/or gastric mucosa; Medications that exacerbate GERD; The pattern of both prescription and non-prescription NSAID use and patients who will require gastric protection; Patients who are experiencing recurrence or complications of PUD or GERD; Significant drug-drug interactions and adverse effects; Patients who are not adhering to a prescribed regimen; Optimal administration and scheduling of medications and alternative forms of oral dosing. The role of the pharmacist as patient advocate and educator cannot be overstated. CONCLUSION Important insights are gained as more literature is published about acid-related disorders and dyspepsia. Acid-related disorders include a broad spectrum of 8 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

9 disease and severity, with dyspepsia the most common presenting symptom of all acid-related disorders. Proton pump inhibitors remain the cornerstone of medical therapy. The majority of patients will need empiric therapy after a thorough clinical history and symptom description is established. This educational module attempts to highlight important information and evidencebased updates on the management of uninvestigated dyspepsia, GERD and PUD and how this information can be applied to the Canadian population. Pharmacists are in a unique and key position, through patient education and collaboration with other health-care providers to optimize the care of patients with acid-related disorders. REFERENCES 1.Veldhuzyen van Zanten S, Flook N, Chiba N, Armstrong D, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. CMAJ 2000;162(12 Suppl):S Talley NJ, Stanghellini V, Heading R, Koch KL, et al. Functional gastroduodenal disorders. Gut 1999;45 (Suppl 2):I Armstrong D, Marshal JK, Chiba N, Enns R, et al. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - update Can J Gastroenterol 2005;19(1): Tougas G, Chen Y, Hwang P, Liu M, Eggleston A. Prevalence and impact of upper gastrointestinal symptoms in the Canadian population: Findings from the DIGEST study. Domestic/International Gastroenterology Surveillance Study. Am J Gastroenterol 1999;94: Revicki D, Wood M, Maton P, Sorensen S. The impact of gastroesophageal reflux disease on healthrelated quality of life. Am J Med 1998;104: Thomson A, Barkun A, Armstrong D, et al. The prevalence of clinically significant endoscopic findings in primary care patients with uninvestigated dyspepsia: The Canadian Adult Dyspepsia Empiric Treatment - Prompt Endoscopy (CADET-PE) study. Aliment Pharmacol Ther 2003;17: Kitchin LI, Castell DO. Rationale and efficacy of conservative therapy for gastroesophageal reflux disease. Arch Intern Med 1991;151; Dent J, Brun J, Fendrick A, et al. An evidencebased appraisal of reflux disease management - the Genval Workshop Report. Gut 1999; 44(Suppl 2): S De Vault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100: Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995;333: van Inxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastrooesophageal reflux disease-like symptoms and endoscopy negative reflux disease (Cochrane Review). Cochrane Database Syst Rev 2005:Vol 2: Available in The Cochrane Library. 12. van Inxteren B, Numans M, Lau J, et al. Short term treatment of gastroesophageal reflux disease. J Gen Intern Med 2003; 18: Armstrong D, Veldhuyzen van Zanten SJO, Barkun AN, Chiba N, et al. Heartburn-dominant, uninvestigated dyspepsia: A comparison of PPI-start and H2-RA start management strategies in primary care - the CADET-HR Study. Aliment Pharmacol Ther 2005;21: Veldhuyzen van Zanten SJO, Chiba N, Armstrong D, Barkun A, et al. A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in Helicobacter pylori negative, primary care patients with dyspepsia: The CADET-HN study. Am J Gastroenterol 2005;100: Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: A meta-analyses. Gastroenterology 1997;112: Carlsson R, Dent J, Watts R, et al. Gastrooesophageal reflux disease in primary care: An international study of different treatment strategies with omeprazole. International GORD Study Group. Eur J Gastroenterol Hepatol 1998;10: Miner P, Katz PO, Chan Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole: A five way crossover. Am J Gastroenterol 2003; 98(12): Vakil N, Fennerty MB. Direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther 2003; Veldhuyzen van Zanten SJO, Bradette M, Chiba N, Armstrong D, et. al. Evidence-based recommendations for short- and long-term management of uninvestigated dyspepsia in primary care: An update of the Canadian Dyspepisa Working Group (CanDys) clinical management tool. Can J Gastroenterol 2005;19(5): Sampliner RE. The Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett s esophagus. Am J Gastroenterol 2002;97: Frazzoni M, De ME, Grisendi A, Savarino V. Effective intro-oesophageal acid suppression in patients with GERD: Lansoprazole vs pantoprazole. Aliment Pharmacol Ther 2003; 17: Fass R, Murphy U, Hayden C, et al. Omeprazole 40 mg once a day is equally effective as lansoprazole 30 mg twice a day in symptom control of patients with GERD who are resistant to conventionaldose lansoprazole therapy - a prospective, randomized, multi-centre study. Aliment Pharmacol Ther 2000; 14: Cremonini F, Wise J, Moayyedi P, Talley NJ. Diagnostic and therapeutic use of Proton pump inhibitors in non-cardiac chest pain: a meta-analysis. Am J Gastroenterol 2005; 100: Wang WH, Huang, JQ, Zheng GF, Wong WM, et al. Is Proton pump inhibitor testing an effective approach to diagnose gastroesophageal reflux disease in patients with noncardiac chest pain? A metaanalysis. Arch Int Med 2005; 165: Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch s postulates for pyloric Campylobacter. Med J Aust 1985;142: McColl K, Murray L, El-Omar E, Dickson A, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339: Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001; 134: Talley NJ, Janssens J, Lauritsen K, et al. Eradication of Helicobacter pylori in functional dyspepsia: randomised, double blind placebo controlled trial with 12 months follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. BMJ 1999; 318: Blum AL, Talley NJ, O Morain C, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998; 339: Soo S, Moayyedi P, Deeks J, Delaney B, et al. Psychological interventions for non-ulcer dyspepsia. Cochrane Database Syst 2003;(2):Available in The Cochrane Library. 31.Moayyedi P, Soo S, Deeks J, Delaney B, et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst 2005;(2): Available in The Cochrane Library. 32. Kuipers EJ, Thijs JC, Festen HP. The prevalence of Helicobacter pylori in peptic ulcer disease. Aliment Pharmacol Ther 1995;9(Suppl 2): Ontario Program for Optimal Therapeutics. Ontario guidelines for peptic ulcer disease and gastroesophageal reflux. June Shiotani A, Graham DY. Pathogenesis and therapy of gastric and duodenal ulcers disease. J Med Clin N Am 2002;86: American Gastroenterological Association medical position statement: Evaluation of dyspepsia. Gastroenterology 1998;114: Silverstein F, Graham D, Senior J, Davies H, Struthers B, Bittmann R, Geis G. Misoprostol reduces gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123; Williams MP, Pounder RE. Helicobacter pylori: from the benign to the malignant. Am J Gastroenterol March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 9

10 1999;94(11 Suppl):S Cave DR. Transmission and epidemiology of Helicobacter pylori. Am J Med 1996;100(5A):12-8S 39. Hunt R, Thomson ABR. Canadian Helicobacter pylori consensus conference. Can J Gastroenterology 1998;12: Howden CW. Clinical expressions of Helicobacter pylori infection. Am J Med 1996;100 (5A):27-32S. 41.Asaka M, Takeda H, Sugiyama T. What role does Helicobacter pylori play in gastric cancer? Gastroenterology 1997;113(6 Suppl):S Hunt R, Fallone C, Veldhuyzan van Zanten S, Sherman P, Smaill F, Flook N, et al. Canadian Helicobacter study group consensus conference: Update on the management of Helicobacter pylori - An evidence-based evaluation of six topics relevant to clinical outcomes in patients evaluated for H pylori infection. Can J Gastroenterol 2004;18(9): Chiba N, Velduyzen van Zanten SJO. 13C-urea breath tests are the non-invasive method of choice for Helicobacter pylori detection. Can J Gastroenterol 1999;13: Tytgat GN. Current indications for Helicobacter pylori eradication therapy. Scand J Gastroenterol 1996;31(Suppl 215): Gene E, Calvet X, Azagra R, Gisbert JP. Triple vs quadruple therapy for treating Helicobacter pylori infection: A meta-analysis. Aliment Pharmacol Ther 2003;17: Fischback LA, Goodman KJ, Feldman M, Aragaki C. Sources of varioation of Helicobacter pylori treatment success in adults worldwide: A meta-analysis. Int J Epidemiol 2002;31: Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther 2000;14: Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the United States: The Surveillance of H pylori Antimicrobial Resistance Partnership (SHARP) study, Ann Intern Med 2002;136(1): Best L, Cooper-Lesins G, Haldane D, et al. Helicobacter pylori antibiotic resistance in Canadian populations. (Abstr) Gastroenterology 2004;126: S Nista EC, Candelli M, Fini L. 10 days levofloxacin-based triple therapy in second line treatment for Helicobacter pylori eradication. (Abstr) Gastroenterology 2004;126:S Gatta L, Ricci C, Zullo A. High eradication rate with a rescue levofloxacin based treatment for Helicobacter pylori. (Abstr) Gastroenterology 2004; 126:S Del Valle J, Chey WE, Scheiman J. Acid peptic disorders. In: Yamada T,Alpers D, Kaplowitz N, et al, eds. Textbook of Gastroenterology, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2003: Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340: Chan FK, Leung WK. Peptic ulcer disease. Lancet 2002;360: Hawkey Cj. Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 2000;119: Laine L. Approaches to nonsteroidal antiinflammatory drug use in the high-risk patient. Gastroenterology 2001;120: Chan FK, Graham KY. Review article: Prevention of nonsteroidal anti-inflammatory drug gastrointestinal complications-review and recommendations based on risk assessment. Aliment Pharmacol Ther 2004;19: Derry S, Loke YK. Risk of gastrointestinalhaemorrhage with long-term use of aspirin: Meta analysis. Brit Med J 2000;321: Sorensen HT, Mellemkjaer L, Blot WJ. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol 2000;95: Micklewright R, Lane S, Linley W. Review article: NSAIDs, gastroprotection and cyclooxygenase-iiselective inhibitors. Aliment Pharmacol Ther 2003; 17: Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. The Cochrane Database of systematic reviews. The Cochrane Collaboration Lanas A, Fuentes J, Benito R. Serrano P, Bajador E, Sainz R. Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther 2002; 16: Silverstein FE, Graham DY, Senior JR. Misoprostol reduces serious gastrointestinal complications in patients with RA receiving nonsteroidal anti-inflammatory drugs: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: Yeomans ND, Tulassay Z, Juhasz L. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. N Engl J Med 1998;338: Hawkey CJ, Karrasch JA, Szczepanski L. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. Omeprazole versus misoprostol for NSAIDinduced ulcer management study group (OMNIUM). N Engl J Med 1998;338: Graham DY, Agrawal NM, Campbell DR. Ulcer prevention in long-term users of nonsteroidal antiinflammatory drugs: Results of a double-blind, randomized, multicenter, active - and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002;162: Silverstein FE, Faich G, Goldstein JL. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000;284: Bombardier C, Laine L, Reicin A. Comparison of upper intestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: Systematic review of randomized controlled trials. Br Med J 2002;325: Chan FK, Hung LC, Suen BY. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent bleeding in patients with arthritis. N Engl J Med 2002;347: Chan FK, Hung LC, Suen BY, Wong V, Hui A, Wu J, et al. Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial. Gastroenterology (4): Lai K, Chu K, Hui W, Wong B, Hu W, Wong W, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J med (11): Laine L, Bombardier C, Hawkey CJ. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: Results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002;123: Dubois RW, Melmed GY, Henning JM, Laine L. Guidelines for the appropriate use of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2-specific inhibitors, and proton pump inhibitors in patients requiring chronic anti-inflammatory therapy. Aliment Pharmacol Ther 2004;19: Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long-term use of aspirin: Metaanalysis. Br Med J 2000;321: Labenz J, Peitz U, Kohl H, Kaiser J, Malfertheiner P, Hackelsberger A, Borsch G. Helicobacter pylori increases the risk of peptic ulcer bleeding: A case-control study. Ital J Gastroenterol Hepatol 1999;31: Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen K. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal antiinflammatory drugs: A case-control study. Gastroenterology 1999;116: Ng TM, Fock KM, Khor JL, Teo EK, Sim CS, Tan AL, Machin D. Non-steroidal anti-inflammatory drugs, Helicobacter pylori and bleeding gastric ulcer. Aliment Pharmacol Ther 2000;14: Papatheodoridis GV, Papadelli D, Cholongitas E, Vassilopoulos D, Mentis A, Hadziyannis SJ. Effect of Helicobacter pylori infection on the risk of upper gastrointestinal bleeding in users of non-steroidal antiinflammatory drugs a prospective, case-control study. Am J Med 2004;116: Laine L, Marin-Sorensen M, Weinstein WM. Nonsteroidal anti-inflammatory drug associated gastric ulcers do not require Hepicobacter pylori for their development. Am J Gastroenterol 1992;87: Cullen DJ, Hawkey GM, Greenwood DC, Humphreys H, Shepherd V, Logan RF, Hawkey CJ. 10 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

11 Peptic ulcer bleeding in the elderly: Relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut 1997;41: Loeb DS, Talley NJ, Ahlquist DA, Carpenter HA, Zinsmeister AR. Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: The role of Helicobacter pylori infection. Gastroenterology 1992;102: Pilotto A, Leandro G, Di Mario F, Franceschi M, Bozzola L, Valerio G. Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly: A case-control study. Dig Dis Sci 1997;42: Stack WA, Atherton JC, Hawkey GM, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002;16: Santolaria S, Lanas A, Benito R, Perez-Aisa M, Montoro M, Sainz R. Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users. Aliment Pharmacol Ther 1999;13: Hunt RH, Bazzoli F. Should NSAID/low-dose aspirin takers be tested routinely for H pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing. Aliment Pharmacol Ther 2004;19(Suppl 1): Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal antiinflammatory drugs in peptic-ulcer disease: A metaanalysis. Lancet 2002;359: Malfertheiner P, Megraud F, O Morain C, Hungin AP, Jones R, Axon A, Graham DY, Tytgat G. Current concepts in the management of Helicobacter pylori infection-the Maastricht Consensus Report. Aliment Pharmacol Ther 2002;16: Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114: QUESTIONS 1. Which case best characterizes a patient with heartburn that a pharmacist should refer to a physician for further medical evaluation? a) 50-year-old man who awakens at night with heartburn, coughing, and choking b) 20-year-old student complaining of indigestion after eating pizza c) 40-year-old woman who has heartburn once a month d) 35-year-old man taking OTC H 2 RAs for one week 2. What alarm features should trigger investigation according to the Clinical Management Tool of the CanDys Uninvestigated Dyspepsia guidelines? Choose the best answer. a) Diarrhea, vomiting, anemia, odynophagia b) Vomiting, bleeding/anemia, abdominal mass/weight loss, dysphagia c) Shortness of breath, chest pain, weight loss, tinnitus d) Night sweats, heartburn, regurgitation, shortness of breath 3. Dyspepsia is one of the most common symptom complexes in patients with acid-related disorders. a) True b) False 4. Which statement(s) regarding the epidemiology and impact of GERD is/are TRUE? I. A significant percentage of adults report monthly heartburn symptoms. II. Patients with GERD report significant impairment in quality of life. III. Extraesophageal presentations should rule out GERD. IV. Heartburn and regurgitation are the cardinal symptoms of GERD. a) I, II, and III b) II and III c) I and III d) I, II and IV 5. Which statement(s) regarding the mechanisms of disease of GERD is/are FALSE? I. The main cause of GERD is contact of the esophageal epithelium with the acidic contents of the stomach. II. GERD symptoms may be caused by a combination of lower esophageal sphincter dysfunction, esophageal dysmotility and /or delay in gastric emptying. III.The severity of GERD symptoms is directly related to the degree or severity of erosive esophagitis. IV. Drug therapy targeting the underlying motility disorder of the esophagus is largely successful. a) I, II, and III b) III and IV c) I and III d) IV only 6. Which statement(s) regarding the clinical presentation and diagnosis of GERD is/are TRUE? I. Endoscopy and biopsy are the gold standard for diagnosis of GERD. II. All patients with GERD have erosive esophagitis. III. Dysphagia, weight loss, and hematemesis are alarm symptoms that should immediately prompt further testing for complications of GERD, such as stricture, ulcer or adenocarcinoma. IV. GERD is considered a progressive disease, with progression of both symptoms and esophagitis in all patients. a) I, II, and III b) I and III c) II and IV d) III only CASE STUDY ND is a 47-year-old male who presents to his family doctor with a three-month history of epigastric discomfort. His vitals are normal and his examination is unremarkable. He is approximately 290 lbs, approximately 30% over his ideal body weight and has an erratic eating schedule due to his job. He had been taking OTC antacids and famotidine 40 mg for approximately two months but has not experienced any significant relief. He denies any bleeding, vomiting or NSAID use. 7. How should the primary care physician respond to this patient? a) Treat the patient with eradication regimen that includes antibiotics since H pylori can be the culprit. b) Suggest lifestyle modifications, prescribe a PPI for four weeks and then reassess. c) Refer the patient to a gastroenterologist for endoscopy. d) Suggest lifestyle modifications and continue OTC antacids and/or H 2 RAs for symptomatic relief. 8. ND returns to the clinic for followup. The physician gives the patient a urea breath test and he tests negative for H pylori. His symptoms have lessened, but have not completely March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective 11

12 QUESTIONS continued resolved. What recommendation would be appropriate to provide to the primary care physician? a) Treat the patient with an eradication regimen that includes antibiotics since H pylori can be the culprit despite a negative test. b) Refer the patient to a gastroenterologist for endoscopy. c) Continue current management and reassess after another four weeks. d) Add H 2 RA to the current regimen for four weeks and reassess. 9. Which statement(s) regarding Barrett s esophagus and esophageal adenocarcinoma is/are TRUE? I. Barrett s esophagus is associated with long-standing (chronic) reflux and a risk factor for esophageal adenocarcinoma. II. The risk of adenocarcinoma is extremely high, especially in patients with Barrett s esophagus. III. Treatment of GERD with PPIs has been shown to decrease the incidence of Barrett s esophagus. IV. Patients who have had chronic reflux for more than 10 years should receive a once in a lifetime endoscopy to assess for Barrett s esophagus. a) I, II and III b) II and III c) I and IV d) all of the above 10. Since few trials have directly compared different PPIs, whether the different pharmacokinetic properties of these drugs translate into significant clinical differences is unknown. a) True b) False 11. Clinical studies indicate that the most effective acid-suppression medications belong to which class of drugs? a) Antacids b) PPIs c) H 2 RAs d) Sucralfate 12. Proton pump inhibitors have been shown to play a significant role in: a) Eradicating H pylori in the context of a triple therapy with antibiotics; b) Protecting against NSAID-induced duodenal ulcers, not gastric ulcers; c) None of the above. d) (a) and (b) 13. H pylori is a pathogen associated with the development of: a) GERD b) NSAID-induced ulcers c) PUD d) All of the above 14. Mark, a 39-year-old construction worker, had symptoms of PUD and was found to be H pylori positive. He received triple therapy treatment with lansoprazole + clarithromycin + amoxicillin (HP-PACÆ) for 2 weeks and his symptoms resolved. Future treatment options for Mark include: a) Intermittent PPI or H 2 RA for recurrent symptoms. b) Diovol PRN. c) Chronic acid suppression with H 2 RA or PPI. d) No treatment. 15. Which statement about therapy with NSAIDs is TRUE? a) COX-2 inhibitors have not been associated with risk of cardiovascular events. b) Standard dose H 2 RAs are effective in reducing the risk of NSAID-induced gastric ulcers. c) Patients >65 starting on meloxicam therapy should receive PPI or misoprostol co-therapy, or switch to celecoxib. d) Low-dose ASA is not associated with an increased risk of upper GI bleeding. 16. Which statement about prophylaxis in patients treated with NSAIDs is FALSE? a) Co-therapy with a PPI has been shown to reduce the incidence of gastroduodenal ulcers. b) Standard dose H 2 RAs (e.g. famotidine 20 mg bid) are not indicated in the prevention of gastric ulcers. c) Low-dose misoprostol (e.g. 200 mcg bid) is as effective as a PPI with a low incidence of side effects. d) PPI therapy has been shown to be effective for treating NSAID-associated GI ulcer complications. 17. Martha, a 47-year-old school teacher, presents with a recent onset of heartburn, gnawing, abdominal pain that has been causing discomfort. She denies vomiting, blood in her stool or recent weight loss. She takes HCTZ 25 mg daily for hypertension and recently naproxen 550 mg intermittently for lower back pain. What is the best initial treatment option? a) Check H pylori serology status. b) Stop intermittent naproxen use and suggest acetaminophen. c) Treat empirically with sulcrafate. d) Refer to GI specialist for upper endoscopy. 18. Burt is a 68-year-old retired engineer presenting with a recent history of epigastric symptoms. He has experienced a 10-pound weight loss in the past 3 months. Upon further examination, he is found to have a heme-positive stool. What is the best approach? a) Check H pylori stool antigen. b) Check H pylori serology. c) Endoscopy d) Empiric triple therapy with PPI + 2 antibiotics 19. For the prevention of DU recurrence after initial ulcer healing, which statement below about H pylori eradication treatment is TRUE? a) H pylori eradication treatment in addition to acid suppressive therapy is superior to acid suppressive therapy alone. b) PPI therapy is superior to H pylori eradication. c) Neither strategy is very effective. d) There is no significant difference between the 2 treatment options. 20. Simon, a 32-year-old stockbroker, presents to the clinic with burning mid-epigastric discomfort that is relieved with Tums, which he has been using daily. H pylori testing is positive by urea breath testing. Simon has no known drug allergies. Treatment options include: a) PPI + amoxicillin + metronidazole x 10 days b) PPI + levofloxacin + amoxicillin x 10 days c) PPI + amoxicillin + clarithromycin x 7 days d) Ranitidine HCl + amoxicillin + tetracycline x 14 days 12 Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

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