Update on the Management - Canadian Healthcare Network · March 2006 Update on the Management of Acid-Related Disorders: ... as those at high risk of other GI ulcer complications

March 2006 Update on the Management of Acid-Related Disorders: A Canadian Perspective | 1

INTRODUCTIONDyspepsia is the main manifestation ofacid-related conditions: functional ornon-ulcer dyspepsia (FD/NUD), gas-troesophageal reflux disease (GERD),peptic ulcer disease (PUD) and gastric,esophageal or pancreatic cancer. Theprevalence of dyspepsia in Canada hasbeen estimated at approximately 29%and may be as high as 50% in Westerncountries.1 It significantly decreaseshealth-related quality of life and inCanada, over $670 million is spent onmedication alone.2,3

Dyspepsia is a symptom complexrather than a disease and its definitionhas evolved over the last decade. It is dif-ficult to establish a unifying definition of

dyspepsia since subjective symptoms andtheir interpretation vary betweenpatients, physicians and even culture andlanguage. The Canadian Dyspepsia(CanDys) Working Group defines dys-pepsia as “a symptom complex of epigas-tric pain or discomfort thought to origi-nate in the upper gastrointestinal tract,and [which] may include any of the fol-lowing symptoms: heartburn, acid regur-gitation, excessive burping and/or belch-ing, increased abdominal bloating, nau-sea, feeling of abnormal or slow diges-tion or early satiety.”1

The majority of patients with symp-toms of upper gastrointestinal (GI) dis-comfort will present to the communitypharmacy or family physician seeking

A FREE CONTINUING EDUCATION LESSON

Update on the Managementof Acid-Related Disorders: A Canadian PerspectiveBy Doret Cheng, BScPharm, PharmD and Lisa Burry, BScPharm, PharmD, FCCP

Doret Cheng is an internal medicine clinical pharmacy specialist with an active clinical and researchpractice at Mount Sinai Hospital in Toronto. Doret is the Medicine Clinical Coordinator at Mount Sinaiwhere she deals with patients with dyspepsia as well as those with GI bleeding and other ulcer compli-cations. Doret is currently leading a working group on an initiative to improve GI acid suppressive prac-tices 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 inthe Medical-Surgical Intensive Care Unit at Mount Sinai Hospital in Toronto She is also the SurgicalClinical Coordinator for Mount Sinai Hospital. Lisa deals with patients with active GI bleeding as wellas those at high risk of other GI ulcer complications. Lisa has provided many presentations to phar-macists and physicians on the management of variceal and non-variceal GI bleeding and is currentlyworking with Doret Cheng on an initiative to improve GI acid suppressive practices at Mount SinaiHospital. 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 orpotential conflict of interest with the sponsor of this lesson.

SUPPORTED BY AN EDUCATIONAL GRANT FROM

OBJECTIVESThis professional development activ-ity shares the clinical experience ofexperts, demonstrates best clinicalpractices, and highlights new clini-cal trials pertaining to the manage-ment of GI acid-related disorders.At the completion of this activity,pharmacists should be able to:1. recognize the clinical impact of acid-

related disorders and associated GImucosal injury;

2. outline management strategies forpatients with uninvestigated dyspepsia,GERD (erosive and non-erosive) andPUD;

3. identify candidates for GI prophylaxisin the setting of ASA/NSAID therapy;

4. discuss the role of the pharmacist inmanaging patients with, or at risk for,acid-related disorders.

INSTRUCTIONS1. After carefully reading this lesson, studyeach question and select the one answeryou believe to be correct. Circle the appro-priate letter on the attached reply card.2. Complete the card and mail, or fax to (416) 764-3937.3. Your reply card will be marked and you will be advised of your results withinsix 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 individualpharmacists to notify them.)

Approved for 1.5 CE unitsby the Canadian Councilon Continuing Education inPharmacy. File #327-1105.

THIS FREE LESSONIS APPROVED FOR1.5 CE UNITS

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2 | Update on the Management of Acid-Related Disorders: A Canadian Perspective March 2006

advice and/or a diagnosis. It is thereforecrucial that pharmacists recognize thetypical signs and symptoms and moreimportantly the alarm features forappropriate recommendations and refer-ral. Pharmacists are in a prime positionto identify patients who have an acid-related gastrointestinal disorder, to assesstheir level of risk for complications, toeducate patients on self-management,and to optimize care through collabora-tion with patients and physicians.

DETECTION & MANAGEMENT OF GASTROINTESTINAL ACID-RELATED DISORDERS A) Uninvestigated dyspepsiaPrior to investigational work-up,patients with dyspeptic symptoms areconsidered to have uninvestigated dys-pepsia. The CanDys Working Group,consisting of a multidisciplinary groupof specialists, family physicians andpharmacists, developed a clinical man-agement tool (CMT) based on bestavailable evidence and expert opinion forpatients who present with new-onset orrecurrent dyspepsia.1 This tool providesthe primary-care physician with five keyquestions to stratify and manage patientsbased on clinical features and symptoms(Fig 1). A unique feature of this tool isthat it highlights and prompts the physi-cian to address the importance of possi-ble non-GI causes of dyspeptic symp-toms, which will require further investi-gation. The alarm symptoms requiringurgent investigation include vomiting,evidence of gastrointestinal blood loss oranemia, abdominal mass or involuntaryweight loss, dysphagia, odynophagia andchest pain.3 These symptoms may besuggestive of an organic cause and phar-macists should advise patients to contacttheir physicians immediately for furtherinvestigation.

B) GERDGastroesophageal reflux disease (GERD)is defined as “reflux of gastric contentsinto the esophagus causing symptomssufficient to reduce quality of life and/oresophageal injury.”3 It is the most com-mon gastrointestinal and acid-relateddisorder in Canada. In a survey of over1,000 Canadians, 17% reported heart-burn in the preceding three months and

13% had moderate to severe symptomson a weekly basis.4 Quality of life is sig-nificantly affected, with patients report-ing a poorer quality of life than thosewith diabetes, hypertension, mild heartfailure or arthritis.5

The typical presentation of GERDincludes heartburn and regurgitation.Heartburn may wax and wane, and isusually worsened by lying down andingestion of food. In a recent Canadianstudy (CADET-PE), reflux esophagitiswas by far the most common endoscop-ic finding in patients with uninvestigat-ed dyspepsia regardless of the dominantsymptom reported.6 Most patients withtypical GERD symptoms do not under-go investigation; therefore the term“heartburn-dominant uninvestigateddyspepsia” encompasses GERD.3 Refluxdisease can also produce atypical symp-

toms (extraesophageal manifestations)such as shortness of breath and wheez-ing, cough, pharyngitis, hoarseness, andchest pain (see Table 1).

Symptoms of acid reflux are likelydue to poor gastric emptying and con-tact of esophageal mucosa with acid andpepsin. Structural and physiologicalmechanisms such as the loweresophageal sphincter (LES), bicarbonatein saliva, and esophageal peristalsis formthe body’s anatomic defence againstreflux. LES dysfunction due to transientrelaxations and decreased tone,esophageal peristaltic dysfunction andabnormal gastric emptying may play arole in the development of GERD. Anumber of factors may alter naturaldefence mechanisms and increase therisk of reflux:• Lifestyle factors (e.g. smoking, large

Uninvestigated dyspepsia

Other possible causes?

Consider• Cardiac• Hepatobiliary• Medication-induced• Dietary indiscretion• OtherTreat as appropriate

Is dominant symptom heartburn or regurgitation?

Hp test positive?1. UBT

2. SerologyTreat as

Hp negative

NSAID and/or regularASA use?

Investigate (Endoscopyrecommended)

Treat as NSAID-induced(See section on peptic

ulcer disease)

Treat as GERD (see section on GERD)

Treat as Hp positive

Age >50 or alarm features?• Vomiting• Bleeding/anemia• Abdominal mass/

unexplained weight loss• Dysphagia

FIGURE 1:

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

NO

NO

NO

NO

NO

NO

YES

YES

YES

YES

YES

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meals, fatty foods, caffeine, pregnancy,obesity, body position and estrogen)

• Medications that lower LES pressureor cause direct GI irritation (Table 2)

• Hiatus hernia (increased esophagealexposure to gastric contents)The severity of symptoms and degree

of mucosal damage correlates with dura-tion of exposure of the esophagus to gas-tric acid (duration of time pH<4).3

Therapies that prolong gastric acid sup-pression are therefore desirable for fastersymptom relief and improved healingrates.

Lifestyle modification appears to havelimited effectiveness for patients withsevere and frequent GERD and well-designed controlled trials are needed tomake any definitive conclusions regard-ing clinical efficacy.7 Despite the sparse-ness of controlled data, clinical experi-ence suggests that patients with mildsymptoms would likely benefit fromstrategies such as elevating the head ofthe bed, avoiding lying down within twohours of eating, avoiding food and med-ication triggers, reducing weight, quit-ting smoking, and decreasing coffee andalcohol consumption.3,7

Various comparative trials haveshown that over-the-counter antacidsalone or combined with low-dose hista-mine-2 receptor antagonists (H2RAs;e.g. ranitidine 75 mg or famotidine 10 mg) and antireflux agents such asalginic acid and are effective for symp-tom relief in mild GERD.3,7,8 There issuggestion that antacids provide quickrelief and OTC H2RAs provide a longerduration of relief.9 There are very fewwell-designed studies comparing OTCH2RAs and antacids; however, due tothe availability and safety profile of theseagents, they are reasonable alternativesfor patients with very mild and infre-quent symptoms, particularly if symp-toms are associated with meals or trig-gered by certain foods.3

Prokinetic or promotility agents suchas cisapride, metoclopramide and dom-peridone have been studied in the treat-ment of GERD. These agents have beenproposed to peristalsis and LES tone.Cisapride is the only prokinetic agentthat has shown clinical efficacy10; howev-er, it is no longer available on the marketin Canada and is now only available

through the special access program dueto concerns about prolongation of QTinterval, ventricular tachycardia anddeath. Due to the paucity of clinicallyrelevant data, these agents are not recom-mended alone or in combination withanti-secretory agents for the long-termmaintenance treatment of GERD.3,11

The 2004 Canadian GERD Consensusguidelines recommend that a once-dailyproton pump inhibitor (PPI) should beused for the empirical treatment ofGERD unless symptoms are mild andinfrequent (i.e. fewer than three timesper week).3 This recommendation is supported by a meta-analysis of 13 trialsin more than 3,000 patients where PPIs were approximately twice as effec-tive as H2RAs.12 Furthermore, 2 recentCanadian studies showed that PPIs pro-vide the highest rate of relief during thefirst 2-4 weeks of therapy compared toH2RAs.13,14

The CADET Heartburn-Dominant(CADET-HR) study13 compared heart-burn relief in patients with uninvestigat-ed dyspepsia with PPI or an H2RA.Three-hundred and ninety patients wererandomized to either omeprazole 20 mgdaily or ranitidine 150 mg twice dailyfor the first 4-8 weeks, with an escalationin therapy to omeprazole 40 or 20 mg,respectively if symptoms persisted.Results indicated that a PPI providesbetter symptom relief at 4 weeks, but nodifference was observed for subsequentrelapses during a 6-month treatment-free follow-up period. Forty-seven per-cent (47%) of patients on ranitidinerequired escalation therapy due to inad-equate heartburn relief, compared to26% of patients who had started withomeprazole. At 4 weeks, the differencein heartburn relief was 27.8% in favourof PPI-start strategy (55.1% vs. 27.3%,p<0.001). The difference in mediantimes to sustained heartburn resolutionwas 24 days in favour of PPI (5 vs. 29days), and at 4 weeks the PPI-start strat-egy was better in achieving additionalheartburn relief and sustained effect(NNT = 4).

The multi-centre CADET-HNstudy14 comparing omeprazole, raniti-dine, cisapride, or placebo in H pylori-negative primary-care patients with dys-pepsia was recently published, providing

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. Extraesophagealgastroesophageal reflux disease.Gastroenterol Clin North Am 1999;28:861-73.

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. Thediagnosis and management of gastroe-sophageal reflux disease. Med Clin NorthAm 1996; 80: 411-29.

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more evidence that PPIs provide bettersymptom relief compared to H2RAs andmotility agents. Five-hundred andtwelve patients were randomized to 4weeks of treatment with omeprazole 20mg daily, ranitidine 150 mg twice daily,cisapride 20 mg twice daily or placebofollowed by on-demand therapy for anadditional 5 months. The study’s pri-mary outcome measure was the GlobalOverall Severity (GOS) score at 4 weeks,measuring dyspepsia symptoms. At base-line, included patients reported at leastmoderate symptom severity (GOS atleast 4/7). A score of 1 or 2 defined treat-ment success. Treatment success at 4weeks was omeprazole 51.1%, ranitidine36%, cisapride 30.5% and placebo23.3% (NNT = 4, omeprazole vs. place-bo; NNT = 7, omeprazole vs. raniti-dine). At 6 months there were no statis-tically significant differences betweengroups in terms of symptom relief.

Evidence of erosive esophagitis (EE)on endoscopy accounts for up to two-thirds of patients with symptoms ofreflux or 5 to 12% of the general popu-lation.3 The presence and severity of EEdoes not correlate with the severity ofsymptoms, however there is a correlationwith complications such as esophagealstrictures and Barrett’s esophagus (BE).Severity of EE has been graded using theLA classification system (see Table 3)based on endoscopic evidence. Multiplestudies and meta-analyses provide evi-dence that PPIs in acute and long-termtreatment provide significantly greatersymptom relief and healing compared toH2RAs or cisapride in EE (absolute dif-ferences in healing rates of 30-40%).15 Inaddition, standard dose PPIs (Table 4)are more effective than low-dose PPIs.16

Standard dose PPIs (Table 4) have beencompared in 24-hour intragastric pHstudies. According to a 5-way crossovertrial comparing esomeprazole 40 mg toall other agents at standard doses,esomeprazole provided a longer durationof acid suppression (pH>4).17 At thispoint, no unifying recommendationshave been made regarding choosing onePPI over another since the clinical rele-vance of various direct comparisons isstill under debate.3,18

Barrett’s esophagus (BE), a metaplas-tic change from normal esophageal squa-

Method Comments

Endoscopy not required

Urea Breath Test (UBT) •UBT detects active infection by testing for the enzymatic activityof bacterial ureases.

Blood •Antibodies can be detected from blood, plasma or serum.Serology will remain positive for those previously infected as antibodies remain after eradication.

Fecal antigen •Fecal antigen testing identifies active infection by detecting the presence of antigens in stools.

Endoscopy required

Rapid Urease tests •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

Histology •Culture primarily used in research studiesCulture •Much more invasive and expensive compared to UBT, blood and

fecal antigen testing

Adapted from 33,39

TABLE 5: H pylori diagnostic testing

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 mgRabeprazole 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 BIDRanitidine 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 4: Standard daily doses of proton pump inhibitors and H2RAs1,3

Grade Definition

A One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the mucosal folds.

B One or more mucosal breaks more than 5 mm long; none of which extends between the tops of 2 mucosal folds.

C Mucosal breaks that extend between the tops of 2 or more mucosal folds, but which involve less than 75% of the esophageal circumference.

D Mucosal breaks which involve at least 75% of the esophageal circumference.

Source: Lundell L, Dent J, Bennett J, et al. Endoscopic assessment of oesophagitis: Clinicaland functional correlates and further validation of the Los Angeles classification. Gut1999;45:172-80.

TABLE 3: The Los Angeles classification system for the endoscopic assessment ofesophagitis

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mous epithelium to columnar intestinalepithelium, is a serious complication ofGERD. The incidence of BE increaseswith higher frequency (>3 times perweek), severity and duration (>20 years)of GERD symptoms. BE has been asso-ciated with the development ofesophageal adenocarcinoma; Canadiandata show that the absolute risk of pro-gression to adenocarcinoma in patientswith long-standing GERD is approxi-mately 0.4%.19 Although the likelihoodof gastric or esophageal cancer is relative-ly low, the prevalence of cancer increaseswith age (>50) and with the severity, fre-quency and duration of GERD symp-toms. North American gastroenterologyguidelines recommend lifelong PPI ther-apy for BE patients along with periodicendoscopic surveillance.19,20 A strategycalled “once in a lifetime” endoscopy hasbeen developed for patients with chron-ic GERD, calling for endoscopy after 10years of GERD symptoms to identifypatients who have BE. Notwithstanding,life-long PPI treatment and “once in alifetime” endoscopy has not been shownto reduce the incidence of gastric oresophageal cancer.19

For patients who fail to respond tostandard-dose therapy and/or withsevere esophagitis (LA Grade C or D, orstricture), some may obtain relief withdouble-dose or longer duration of PPItherapy.21,22 Recently, there have beensome data to suggest that high-dose PPItherapy reduces symptoms in patientswith extraesophageal manifestations ofGERD such as non-cardiac chest pain(NCCP). Two meta-analyses showedthat using higher doses of PPI (omepra-zole 40/80 mg or lansoprazole 30 mg)for up to 4 weeks is a useful and poten-tially cost-saving strategy to diagnoseand treat patients with NCCP. The smallnumber of trials and patients included inthese meta-analyses limit their generaliz-ability; therefore more evidence is need-ed to confirm these results.23,24

C) Functional (non-ulcer) dyspepsiaThe diagnosis of functional dyspepsia(FD), also referred to as non-ulcer dys-pepsia (NUD) is defined as 12 weeks ormore of persistent or recurrent dyspepsiawithin the last 12 months plus theabsence of evidence that organic disease

is likely to explain the symptoms(including evidence from upperendoscopy).2 This implies that a com-plete diagnostic evaluation has beencompleted and any obvious structuralabnormality such as PUD or refluxesophagitis has been ruled out.Symptoms are frequently described asulcer-like (e.g. burning) or dysmotility-like (e.g. nausea, bloating, early satiety,anorexia). Several pathophysiologicmechanisms have been proposed: motil-ity abnormalities, visceral sensory abnor-malities, psychological factors or chronicgastritis secondary to infection. One ofthe more prevalent theories currentlybeing investigated is the possible relationbetween Hp infection and FD/NUD.Dyspepsia has been shown to occur afterintentional Hp infection,25 suggesting acorrelation; however, treatment resultshave been inconsistent and the role ofHp in non-ulcer dyspepsia remains con-troversial.26-29

Psychosocial factors (e.g. anxiety,depression and stress) have been shownin epidemiological studies to be moreprevalent in patients with FD/NUD. Asystematic review evaluated the effects ofpsychotherapy, cognitive behaviour ther-apy, relaxation therapy and guidedimagery or hypnosis.30 The 3 trialsincluded in the review showed improve-ment of symptoms at 12 weeks; howev-er, the effect was no different after oneyear. Due to the heterogeneity of thesestudies, the results were not pooled andno specific recommendations werederived. Psychotherapy should be evalu-ated on an individual basis and consid-ered in patients with a significant psy-chiatric condition or as an adjunct tomedical management.

The management of FD/NUD isoften based on the predominant symp-toms patients report. A plethora of datahas been published and recently aCochrane review analyzed 61 pharmaco-logical intervention trials (antacids, bis-muth salts, sucralfate, misoprostol, pro-kinetic agents, H2RAs and PPIs) forNUD.31 Due to trial limitations and sig-nificant heterogeneity, the managementof NUD remains challenging and sub-jective. Nevertheless, indirect compar-isons of the trials suggest that choice oftherapy should be based on individual

dyspepsia symptoms. Prokinetic agentswere significantly better than H2RAs forsymptoms of dysmotility such as nauseaand early satiety, whereas H2RAs werebetter for heartburn. The evidence forantisecretory agents for reflux symptomsis strongest for PPIs as the studies weregenerally of higher methodological quality. However, due to the significantoverlap in patients with symptoms ofGERD and NUD, management of thesepatients mirrors that of GERD. Moreevidence is needed with clear delineationof patients and symptoms before anyconclusions can be made.31

D) Peptic ulcer disease (PUD)A peptic ulcer is a non-malignant lesionin the GI mucosa that may be acute,subacute or chronic. The major formsare duodenal ulcer (DU) and gastriculcer (GU), and it is not uncommon forpatients to develop both simultaneously.Lifetime prevalence is estimated to be 4-10% and is significantly higher in Hp-positive subjects - 10-20%.32-34

In general, a poor correlation existsbetween dyspeptic symptoms and pres-ence of ulcers and there is no symptomcomplex that can adequately differenti-ate between GU, DU and NUD.33,34,36

Patients may experience minimal symp-toms while others have severe initialpresentation. Classic symptoms havebeen described as epigastric painbetween the xiphoid process and theumbilicus or discomfort characterized byfullness, bloating, distention or nau-sea.35,36 Potential complications includehemorrhage (15-20%), perforation(5%), and gastric outlet obstruction(2%).36

Two decades ago, almost all pepticulcers were considered to be idiopathicor due to excess gastric acid, stress ordiet. Although acid injury is necessaryfor ulcers to form, acid secretion is nor-mal in almost all patients with GUs andincreased in only one-third of patientswith DUs. Today, it is well known thatPUD is the end result of a number of eti-ological factors that disrupt GI defence.H pylori infection and NSAIDs are nowwidely accepted as the major contribu-tors to this disequilibrium.33,34 Theremainder of this discussion attempts toupdate the reader on new guidelines or

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clinical trials related to Hp, NSAIDs andthe relationship between the two.

i) H pyloriH pylori infects ~20% of the westernworld’s population; the incidence andprevalence varying with age and eco-nomic status.37,38 Factors associated withan increased prevalence include lowsocio-economic status, poor sanitaryconditions and overcrowding. Up to20% of those infected with Hp are foundto have PUD, with >90% identificationin DUs and 70-85% in GUs.33,39 CuringHp infection will not only reduce theulcer recurrence rate but also the risk oftype-B chronic atrophic gastritis, pepticulcer dyspepsia, and low-grade gastricMALT lymphoma.40-42

H pylori can be detected using eitherinvasive or non-invasive techniques (seeTable 5). Important considerations inselecting a test are availability, accuracy,prior treatment for Hp, cost-effective-ness, the appropriateness of endoscopy,and clinical circumstances that mayaffect the results.39,42 As the incidenceand prevalence of Hp seems to bedecreasing in industrialized nations,including Canada, the role of accuratetesting becomes increasingly importantand primary care diagnostic tests thatwere once adequate need reappraisal.42

The 2004 Canadian H pylori StudyGroup (CHSG) Consensus does not rec-ommend stool antigen tests as an accept-able tool to diagnose infection in com-munity-based practice based on lack ofsufficient evidence and the need for ded-icated and experienced laboratory staff.42

Serology was not considered to be accu-rate in many Canadian populationsbecause, as the prevalence of infectiondeclines, the predictive value of serologywill become less reliable.42,43 For now, theurea breath test remains first choicewhen endoscopy is not indicated.

Since Hp was first cultured from thehuman GI tract in 1984, the relation-ship between it and GI ulcers has beenexplored in >3,000 RCTs, with a multi-tude of data supporting eradication ratesof up to 96% with some regimens.33

Compared with acid suppression alone,Hp eradication therapy has been wellproven to facilitate ulcer healing andreduce ulcer recurrence and complica-

tion rates several-fold.33,42 After successfuleradication of Hp, recurrences of PUDare expected to be <5% annually.33,44

Given the proven importance of eradi-cating infection, finding the “ideal” reg-imen is vital. Single- and dual-agenttherapy should not be used because ofthe unacceptably low eradication rates (<70%). CHSG guidelines suggestsquadruple therapy for 10-14 days is aseffective and well tolerated as 7-10 dayPPI-based triple therapy regimens (seeTable 6).42,45,46 However, given the com-plexity of a quadruple regimen, tripletherapy with a PPI is often made firstchoice in practice. Newer evidence is

emerging to suggest PPI-based triple reg-imens are more effective if administeredfor 14 days, although the increase inbenefits is small (~5%).42,47

Treatment of Hp infection is nowcomplicated by a growing phenomenonof antibiotic resistance, which will nega-tively impact eradication rates and limitthe utility of some of the currentoptions.42 Pre-treatment antimicrobialresistance also has an important negativeimpact on the efficacy of many regi-mens. A recent study from Nova Scotiareported the following pretreatmentresistance rates: clarithromycin, 11%;metronidazole, 19%; tetracycline, 2%;

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 amoxicillinor metronidazole 500 mg bid} •Metronidazole is typically substituted for amoxicillin

for penicillin allergic patients

Quadruple Therapy

H2RA bid or PPI bid •Ranitidine bismuth citrate was discontinued + from the Canadian market in 2000.

Bismuth subsalicylate •Ranitidine should not be substituted for ranitidine (525 mg) ii tab qid bismuth citrate

+ •Duration 14 daysmetronidazole 250 mg qid •Eradication rates of 75-85% in RCTs

or 500 mg tid+

tetracycline 250 mg qid or 500 mg tid

TABLE 6: Regimens for H pylori eradication

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

TABLE 7: Risk Factors for NSAID/ASA-Induced Ulcers and Upper GI Complications

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and amoxicillin, 0%; confirming pub-lished U.S. data.42,48,49

Cases in which the patient has under-gone more than one treatment withoutsuccessful eradication of Hp infection aretypically difficult to manage with lowlikelihood of cure. CHSG suggests susceptibility testing for those who failfirst-line therapy to guide selection ofthe second treatment regimen.42

Traditionally, second-line treatmentshave been quadruple agent regimens.Recently, second-line therapy with a fluoroquinolone-based triple regimen(e.g. levofloxacin 250 mg bid + amoxi-cillin 1 g bid + esomeprazole 40 mg bidfor 10 days) has been explored.50,51

Preliminary results with fluoroquino-lones are promising as eradication rates>80% have been reported but results arestill preliminary and so the use should bereserved for those who have failed first-line treatments.

ii) NSAID-related PUDNSAIDs are the second most commoncause of PUD and ulcer-related upperGI complications.52-55 The most signifi-cant NSAID-associated gastrointestinaltoxicities are peptic ulcers (~40% ofchronic users have endoscopic ulcers)and serious complications (~1.5%) suchas upper GI bleeding and perforations,that result in significant morbidity andmortality.42 Given the widespread useand the incidence of serious GI compli-cations with NSAID (~3%/year), an

exposure of 10 million patients couldresult in 300,000 potentially fatal com-plications annually.33,52,56 Risk factors forulcers and complications secondary toNSAIDs are presented in Table 7.Additive risk is conferred when risk fac-tors are combined.57

Prevention should be considered forthose at increased risk for GI injury orthose who would be at significant riskfor morbidity/mortality if a complica-tion developed. A number of strategieshave been used to reduce the risk ofNSAID-related ulcers and complica-tions: buffering or enteric coating of theNSAID formulation; antacids; sucral-fate; H2RAs; misoprostol; PPIs (seeTable 8). There is insufficient evidenceto support the use of buffer or entericcoating, antacids or sucralfate in reduc-ing the risk of NSAID-related ulcers andtheir complications. H2RA co-therapy has been shown to be effective in reducingthe risk of endcoscopic duodenal but not gastric ulcers. Double-dose H2RAco-therapy was effective at reducing therisk of endoscopic DU and GU.52,53,55-57,60,61

Misoprostol has been shown to reducethe risk of ulcer56-58,60-62 and serious ulcer-related GI complications.57,62 Misoprostol800 mcg/day was superior to 400 mcg/dayfor the prevention of endoscopic gastriculcers; a dose response relationship wasnot seen with duodenal ulcers.52,53,56,61

However, multiple daily dosing, itsuterotrophic effects, abdominal cramp-ing, and dose-related diarrhea limit its

use. The total daily misoprostol dosagemay be reduced to minimize diarrhea,but dosages as low as 400 mcg/day maycompromise its gastroprotective effect.Substantial data has proven concomitantuse of a PPI substantially reduces the riskof DU and GU associated with non-selec-tive NSAIDs compared to various othertherapies56,57,60,61,64-66 Overall, H2RAs andPPIs are better tolerated than misopros-tol, and reduced NSAID related dyspep-tic symptoms.61

An alternative proposed approach hasbeen to use COX-2 selective NSAIDs, asit was previously observed that NSAIDswith greater inhibition of COX-2 versusCOX-1 appeared to be associated with alower prevalence of GI ulceration anderosions on endoscopic evaluation.57,67-69

This review would not be completewithout a brief discussion of the recentCOX-2 trials, despite the fact that in late2004, evidence became available associ-ating COX-2 use with significant cardio-vascular concerns, increased risk of heartattach and stroke, compared with place-bo. Since the publication of this infor-mation celecoxib is the only remainingselective COX-2 agent on the Canadianmarket and is typically avoided in thoseat risk of cardiovascular events. Twolarge multicentre, double-blind trials,CLASS67 and VIGOR,68 examined theGI safety of COX-2 agents. Both trialsused high doses of the specific COX-2inhibitor and selected patients in theCLASS trial received low-dose ASA.Initial analysis of the CLASS andVIGOR trials indicated that both cele-coxib and rofecoxib decreased the risk ofdeveloping upper GI clinical events andcomplications by ~50% when comparedwith traditional agents in patients nottaking concomitant low-dose ASA. Thebeneficial effects of a COX-2 inhibitormay abolish the GI safety of these agentsas suggested in the CLASS study post-hoc analyses.67 The utility of PPIs incombination with non-selective NSAIDversus COX-2 selective inhibitors havebeen explored as a means to reduce therisk of recurrent bleeding in Hp-negativepatients with a recent history of ulcer-related bleeding.70 Results suggest thatusing celecoxib monotherapy is as effec-tive as adding a PPI to a non-selectiveNSAID among patients with a recent

Risk∂ Definition Suggested management

Low <65 yr, no ASA, no prior ulcer or Non-selective NSAID aloneGI 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 preferredstrategy for each group remains uncertain and some of the suggested strategies have notbeen investigated in appropriate clinical trials.Compiled from references 56,57,60-62,73-75

TABLE 8: Strategies for Reducing GI Risk in Patients Receiving Chronic NSAID Therapy

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history of ulcer bleeding.70,71 There isgrowing clinical use of combined COX-2 inhibitors with acid suppressive thera-py or misoprostol, especially in thosewith very high risk of complications orprevious history of PUD events.Although such combination may offertheoretically better GI protection, espe-cially in very high risk circumstances, todate, there are no published outcome tri-als to establish the benefits of these com-binations.61,73

When an active ulcer is suspected orconfirmed, therapy with the NSAIDshould be stopped whenever possibleand smoking should be stopped toimprove healing.33,42,52,53 PPIs are the pre-ferred treatment as they provide a rapidrate of ulcer healing, especially in the set-ting of complicated, large ulcers.32,39,42,52 Ifchronic NSAID therapy must be contin-ued potential options include use of aCOX-2 selective NSAID (e.g. celecox-ib), reducing the dosage of the non-selective agent and/or adding concomi-tant therapy with PPIs or misopros-tol.33,52,60 PPIs are the drugs of choicewhen the NSAID must be continued, aspotent acid suppression is required toaccelerate ulcer healing.52,53,56

iii) H pylori interaction with ASA/NSAIDs An interaction between Hp and NSAIDsis biologically plausible given their dif-ferent mechanisms of disrupting gastricmucosal defense but published data didnot always confirm this.62,76-86 A recent

systemic review demonstrated synergismbetween Hp and NSAIDs for the devel-opment of PUD and ulcer bleeding.87

The risk of PUD was reported to be~60-fold higher in Hp positive NSAIDusers compared with Hp-negative sub-jects not taking NSAID. Moreover, Hpinfection was shown to increase the riskof ulcer bleeding by 1.8-fold, NSAIDuse by 4.85-fold, and the presence ofboth factors by 6.1-fold compared withthe risk of bleeding among Hp-negativesubjects not taking NSAID. Table 9summarizes the published data in thisarea and current clinical practice.56,70,86,88,89

CHSG supports Hp testing and eradica-tion for naïve NSAID users.42,86 A similarstrategy has also been suggested for naïveASA users, although the efficacy of suchan approach has not been confirmed. Inchronic ASA/NSAIDs users, recommen-dations depend on the risk of PUD com-plications56 and the type of NSAID.Based on published data, it is reasonablethat any attempt to eradicate Hp infec-tion should follow ulcer healing in themanagement of chronic NSAID users,although the efficacy of such anapproach remains to be confirmed.84,88

The efficacy of Hp eradication in chron-ic ASA users without a history of PUDcomplications has not been evaluated.

ROLE OF THE PHARMACIST The management of GI acid-related dis-orders continues to evolve with a wealthof literature for both functional and

organic acid-associated conditions. Aspharmacists are often the first health-care professionals encountered by thepatient, we are uniquely positioned toidentify, counsel and monitor patientsrequiring acute or chronic therapy forconditions related to gastric acid.Pharmacists should have a workingknowledge of the pathophysiology ofgastric acid-related diseases, risk stratifi-cation, potential under- and over-treatedacid-disorders, as well as the efficacy andsafety of the available pharmacologicalagents/regimens.

The patient interview should includea patient’s past medical and medicationhistory, the nature and timing of symp-toms and the presence of alarm features.Intervention through education, coun-selling and recommendation of initialnon-prescription therapies such asantacids or H2RAs may be appropriatefor patients at low risk. Collaborationwith physicians is vital when pharmacistsidentify and refer patients with alarmsymptoms. The patient should be edu-cated regarding the disease state and itspotential consequences.

Through medication reviews, phar-macists can identify:• Medications that are ulcerogenic or

promote injury to the esophagealand/or gastric mucosa;

• Medications that exacerbate GERD;• The pattern of both prescription and

non-prescription NSAID use andpatients who will require gastric pro-tection;

• Patients who are experiencing recur-rence or complications of PUD orGERD;

• Significant drug-drug interactions andadverse effects;

• Patients who are not adhering to aprescribed regimen;

• Optimal administration and schedul-ing of medications and alternativeforms of oral dosing.The role of the pharmacist as patient

advocate and educator cannot be over-stated.

CONCLUSIONImportant insights are gained as moreliterature is published about acid-relateddisorders and dyspepsia. Acid-relateddisorders include a broad spectrum of

H pylori Test-&-Treat Long-Term Approach 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 evidenceb) 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

TABLE 9: Strategies for approaching Hp status in the setting of NSAID Therapy

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disease and severity, with dyspepsia themost common presenting symptom ofall acid-related disorders. Proton pumpinhibitors remain the cornerstone ofmedical therapy. The majority ofpatients will need empiric therapy after athorough clinical history and symptomdescription is established. This educa-tional module attempts to highlightimportant information and evidence-based updates on the management ofuninvestigated dyspepsia, GERD andPUD and how this information can beapplied to the Canadian population.Pharmacists are in a unique and keyposition, through patient education andcollaboration with other health-careproviders to optimize the care of patientswith acid-related disorders.

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QUESTIONS1. Which case best characterizes apatient with heartburn that a pharma-cist should refer to a physician for fur-ther medical evaluation?a) 50-year-old man who awakens at

night with heartburn, coughing, andchoking

b) 20-year-old student complaining ofindigestion after eating pizza

c) 40-year-old woman who has heart-burn once a month

d) 35-year-old man taking OTC H2RAsfor one week

2. What alarm features should triggerinvestigation according to the ClinicalManagement Tool of the CanDysUninvestigated Dyspepsia guidelines?Choose the best answer.a) Diarrhea, vomiting, anemia, odynopha-

giab) Vomiting, bleeding/anemia, abdomi-

nal mass/weight loss, dysphagiac) Shortness of breath, chest pain,

weight loss, tinnitusd) Night sweats, heartburn, regurgitation,

shortness of breath

3. Dyspepsia is one of the most com-mon symptom complexes in patientswith acid-related disorders.a) Trueb) False

4. Which statement(s) regarding theepidemiology and impact of GERDis/are TRUE?I. A significant percentage of adults

report monthly heartburn symp-toms.

II. Patients with GERD report signifi-cant 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 IIIb) II and IIIc) I and III d) I, II and IV

5. Which statement(s) regarding themechanisms of disease of GERDis/are FALSE?I. The main cause of GERD is contact

of the esophageal epithelium withthe acidic contents of the stomach.

II. GERD symptoms may be caused bya combination of lower esophagealsphincter dysfunction, esophagealdysmotility and /or delay in gastricemptying.

III.The severity of GERD symptoms isdirectly related to the degree orseverity of erosive esophagitis.

IV. Drug therapy targeting the underly-ing motility disorder of the esopha-gus is largely successful.

a) I, II, and IIIb) III and IVc) I and IIId) IV only

6. Which statement(s) regarding theclinical presentation and diagnosis ofGERD 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 symptomsthat should immediately promptfurther testing for complications ofGERD, such as stricture, ulcer oradenocarcinoma.

IV. GERD is considered a progressivedisease, with progression of bothsymptoms and esophagitis in allpatients.

a) I, II, and IIIb) I and IIIc) II and IVd) III only

CASE STUDYND is a 47-year-old male who presentsto his family doctor with a three-monthhistory of epigastric discomfort. His vitalsare normal and his examination is unre-markable. He is approximately 290 lbs,approximately 30% over his ideal bodyweight and has an erratic eating sched-ule due to his job. He had been takingOTC antacids and famotidine 40 mg forapproximately two months but has notexperienced any significant relief. Hedenies any bleeding, vomiting or NSAIDuse.

7. How should the primary care physi-cian respond to this patient?a) Treat the patient with eradication regi-

men that includes antibiotics since H pylori can be the culprit.

b) Suggest lifestyle modifications, pre-scribe a PPI for four weeks and thenreassess.

c) Refer the patient to a gastroenterolo-gist for endoscopy.

d) Suggest lifestyle modifications andcontinue OTC antacids and/or H2RAsfor symptomatic relief.

8. ND returns to the clinic for follow-up. The physician gives the patient aurea breath test and he tests negativefor H pylori. His symptoms have less-ened, but have not completely

AZ_CE_GI_0306_E 2/22/06 4:07 PM Page 11


QUESTIONS continuedresolved. What recommendation wouldbe appropriate to provide to the pri-mary care physician?a) Treat the patient with an eradication

regimen that includes antibioticssince H pylori can be the culpritdespite a negative test.

b) Refer the patient to a gastroenterolo-gist for endoscopy.

c) Continue current management andreassess after another four weeks.

d) Add H2RA to the current regimen forfour weeks and reassess.

9. Which statement(s) regardingBarrett’s esophagus and esophagealadenocarcinoma is/are TRUE?I. Barrett’s esophagus is associated

with long-standing (chronic) refluxand a risk factor for esophagealadenocarcinoma.

II. The risk of adenocarcinoma isextremely high, especially inpatients with Barrett’s esophagus.

III. Treatment of GERD with PPIs hasbeen shown to decrease the inci-dence of Barrett’s esophagus.

IV. Patients who have had chronicreflux for more than 10 yearsshould receive a “once in a life-time” endoscopy to assess forBarrett’s esophagus.

a) I, II and III b) II and IIIc) I and IVd) all of the above

10. Since few trials have directly com-pared different PPIs, whether the dif-ferent pharmacokinetic properties ofthese drugs translate into significantclinical differences is unknown.a) Trueb) False

11. Clinical studies indicate that themost effective acid-suppression med-ications belong to which class ofdrugs?a) Antacidsb) PPIsc) H2RAsd) Sucralfate

12. Proton pump inhibitors have beenshown 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 associatedwith the development of:a) GERDb) NSAID-induced ulcersc) PUDd) All of the above

14. Mark, a 39-year-old constructionworker, had symptoms of PUD and wasfound to be H pylori positive. Hereceived triple therapy treatment withlansoprazole + clarithromycin + amoxi-cillin (HP-PACÆ) for 2 weeks and hissymptoms resolved. Future treatmentoptions for Mark include:a) Intermittent PPI or H2RA for recurrent

symptoms.b) Diovol PRN.c) Chronic acid suppression with H2RA

or PPI.d) No treatment.

15. Which statement about therapywith NSAIDs is TRUE?a) COX-2 inhibitors have not been asso-

ciated with risk of cardiovascularevents.

b) Standard dose H2RAs are effective inreducing the risk of NSAID-inducedgastric ulcers.

c) Patients >65 starting on meloxicamtherapy should receive PPI or miso-prostol co-therapy, or switch to cele-coxib.

d) Low-dose ASA is not associated withan increased risk of upper GI bleeding.

16. Which statement about prophylaxisin patients treated with NSAIDs isFALSE?a) Co-therapy with a PPI has been

shown to reduce the incidence ofgastroduodenal ulcers.

b) Standard dose H2RAs (e.g. famoti-dine 20 mg bid) are not indicated inthe prevention of gastric ulcers.

c) Low-dose misoprostol (e.g. 200 mcgbid) is as effective as a PPI with alow incidence of side effects.

d) PPI therapy has been shown to beeffective for treating NSAID-associat-ed GI ulcer complications.

17. Martha, a 47-year-old schoolteacher, presents with a recent onset

of heartburn, gnawing, abdominal painthat has been causing discomfort. Shedenies vomiting, blood in her stool orrecent weight loss. She takes HCTZ 25mg daily for hypertension and recentlynaproxen 550 mg intermittently forlower back pain. What is the best ini-tial 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 engi-neer presenting with a recent historyof epigastric symptoms. He has experi-enced a 10-pound weight loss in thepast 3 months. Upon further examina-tion, he is found to have a heme-posi-tive stool. What is the best approach? a) Check H pylori stool antigen.b) Check H pylori serology.c) Endoscopyd) Empiric triple therapy with PPI + 2

antibiotics

19. For the prevention of DU recur-rence after initial ulcer healing, whichstatement below about H pylori eradi-cation treatment is TRUE? a) H pylori eradication treatment in

addition to acid suppressive therapyis superior to acid suppressive thera-py alone.

b) PPI therapy is superior to H pylorieradication.

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 burningmid-epigastric discomfort that isrelieved with Tums, which he has beenusing daily. H pylori testing is positiveby urea breath testing. Simon has noknown drug allergies. Treatmentoptions include:a) PPI + amoxicillin + metronidazole x

10 daysb) PPI + levofloxacin + amoxicillin x 10

daysc) PPI + amoxicillin + clarithromycin x 7

daysd) Ranitidine HCl + amoxicillin + tetracy-

cline x 14 days

AZ_CE_GI_0306_E 2/22/06 4:07 PM Page 12

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Update on the Management - Canadian Healthcare Network · March 2006 Update on the Management of Acid-Related Disorders: ... as those at high risk of other GI ulcer complications