1. Successful Strategies for Managing Acid-Related Disease in Primary Care Col. Roy K.H. Wong, MD Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Chief of Gastroenterology Walter Reed Army Medical Center Washington, DC

2. Key Question In what percentage of your patients with chronic GERD do you consider long-term management strategies? 1. 0%-25% 2. 26%-50% 3. 51%-75% 4. 76%-100% Use your keypad to vote now! ?

3. Faculty Disclosure  Dr Wong: speakers bureau: AstraZeneca, Janssen- Kwoya Co. Ltd, TAP Pharmaceutical Products Inc.

4. Learning Objectives  Identify patients at risk for GI complications of acid-related disorders  Describe effective strategies for managing GERD  Discuss options for minimizing GI risk in patients requiring NSAID therapy GERD = gastroesophageal reflux disorder; GI = gastrointestinal; NSAID = nonsteroidal inflammatory drug.

5. Key Question Which of the following increases a person’s risk of developing esophageal adenocarcinoma? 1. Long-standing GERD symptoms 2. Frequent GERD symptoms 3. Both of the above 4. No study has connected GERD symptom characteristics and adenocarcinoma risk Use your keypad to vote now! ?

6. GastroEsophageal Reflux Disease Esophagitis Barrett’s Metaplasia and Adenocarcinoma Bleeding Stricture Nonerosive GERD (EGD negative) Impairs Quality of Life Extraesophageal GERD Dental Asthma ENT EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat.

7. Barlow WJ, Orlando RC. Gastroenterology. 2005;128:771-778. Dent J, et al. Gut. 2005;54:710-717. DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200. Kahrilas PJ, et al. In: Gastrointestinal and Liver Disease: Pathophysiology/ Diagnosis/Management. 7th ed. Philadelphia, Pa:WB Saunders Co; 2002:599-622. Pathophysiologic Determinants of Esophagitis Severity and Chronicity  Chronic condition usually not attributed to excess acid secretion  Treatment approaches are compensatory, rather than curative  Therapeutic focus is on refluxate causticity GERD Severity ≈ Tissue resistance Acid clearance Causticity of gastric juice N of reflux events   Aggressive Factors Defensive Factors

8. Mild Reflux: NERD Moderate to Severe Reflux: Erosive Esophagitis Severe Reflux: Barrett’s Esophagus NERD = nonerosive reflux disease. Adapted from Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909. Traditional Assumptions Concerning GERD Natural History Spectrum/Progression

9. NERD Erosive Esophagitis Stricture Ulcer GI Bleeding Barrett’s Esophagus Typical and Atypical Symptoms Adenocarcinoma of the Esophagus Evolving GERD “Phenotypic Model” Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909. Pandolfino JE, Shah N. Dig Liver Dis. 2006;38:648-651. Progression Within the Group

10. Association Between GERD Symptom Frequency and Duration N = 1438 (n =189 with esophageal adenocarcinoma). Lagergren J, et al. N Engl J Med. 1999;340:825-831.

11. Summary of Disease Progression Importance of Early Treatment  NERD patients may develop esophagitis on follow-up  However, usually mild esophagitis  Esophagitis may heal in patients who continue to have symptoms on PPI therapy  Left untreated, esophagitis may progress to worse complications, including esophageal ulcer and stricture  Long-standing and frequent GERD symptoms have been shown to increase the risk of esophageal adenocarcinoma PPI = proton pump inhibitor. Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909. Lagergren J, et al. N Engl J Med. 1999;340:825-831.

12. Summary of Disease Progression Barrett’s Esophagus  Barrett’s esophagus can develop after years of reflux disease  However, usually diagnosed on initial endoscopy  Once developed, typically remains despite antireflux therapy  Barrett’s may progress to esophageal adenocarcinoma  However, sizeable proportion of adenocarcinoma diagnoses are made without evidence of Barrett’s Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.

13. Key Question Approximately what percentage of patients presenting to general practices with GERD symptoms have normal mucosa or erythema only on endoscopy? 1. 75% 2. 55% 3. 35% 4. 15% Use your keypad to vote now! ?

14. GERD: Endoscopic Findings in General Practice Percent of patients with: N = 789 patients with GERD. Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.

15. GERD Symptom Profile on Presentation in Primary Care Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.

16. When Is Empiric Therapy Appropriate?  2005 ACG Practice Guidelines: “If the patient’s history is typical for uncomplicated GERD, an initial trial of empirical therapy…is appropriate.”  Rationale:  Classic reflux symptoms (ie, heartburn, regurgitation) have a positive predictive value of >80% for GERD  Regardless of endoscopic findings (erosive vs nonerosive), most patients with typical symptoms are treated with PPIs  Further diagnostic testing should be considered if:  The patient has alarm symptoms  There is no response to empiric therapy  The patient has symptoms of sufficient duration to put him/her at risk for Barrett’s esophagus Age >50 – Controversial Longstanding heartburn – How long? DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.

17. Warning Signs/Alarm Symptoms  Dysphagia  Odynophagia  Persistent vomiting  Anorexia  Unintentional weight loss  Anemia  Fever  Gastrointestinal bleeding (occult or overt) The presence of any of these symptoms indicates the need for further testing DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.

18. Algorithm for Diagnostic Referral in Patients Presenting With GERD Symptoms Typical Symptoms Only  Heartburn  Regurgitation History and Physical Examination Early Referral Symptoms  Dysphagia  Early satiety  Frequent vomiting  GI bleeding  Weight loss Atypical Symptoms  Asthma  Chronic cough  Chronic hoarseness  Nausea and vomiting  Unexplained chest pain Empiric Treatment Diagnostic Testing Katz PO. Am J Gastroenterol. 1999;94(11 Suppl):S3-S10.

19. Additional GERD Diagnostic Techniques  Additional study needed to determine impact of newer techniques of impedence and tubeless pH monitoring on GERD management EAE = esophageal acid exposure. DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200. Endoscopy  Allows for direct visualization of the esophagus  Should be considered at presentation if patients have symptoms of complicated GERD or are at risk for Barrett’s  “Technique of choice” to diagnose these conditions Ambulatory pH Monitoring  Identifies patients with excess EAE and those with symptoms that correlate with esophageal acid  Helps to confirm acid reflux in patients with persistent symptoms without evidence of esophageal mucosal damage, especially when a trial of acid suppression has failed  Monitors control of reflux in patients on therapy but with continued symptoms Esophageal Manometry  Used to guide placement of pH monitoring probes  May be helpful prior to antireflux surgery Barium Esophagram  Not recommended for routine GERD diagnosis  Not accurate for diagnosing Barrett’s  Reasonably accurate for severe esophagitis but much less accurate for mild esophagitis

20. Key Question What overall percentage of patients with erosive esophagitis experience healing of erosions with 8 weeks of standard-dose PPI therapy? 1. <75% 2. 75%-84% 3. 85%-94% 4. 95%-100% Use your keypad to vote now! ?

21. Focus of Medical Management of GERD—Compensatory, Not Curative It’s all about acid!  PPIs  H2RAs  Antacids H 2 RAs = histamine 2 -receptor antagonists.

22. Chiba N, et al. Gastroenterology. 1997;112:1798-1810. Meta-Analysis of PPIs, H 2 RAs, and Placebo for Healing Erosive Esophagitis 0 20 40 60 80 100 2 Total Healed (%) 46812 Therapy (weeks) (5) (8) (5) (9) Placebo (2) (23) (25) (22) H 2 RAs PPIs (4) (27) (3) (26) (2) (n) = Number of studies

23. CI = confidence interval. Caro JJ, et al. Clin Ther. 2001;23:998-1017. Meta-Analysis of PPIs Versus Ranitidine for Healing Erosive Esophagitis Healing Rate Ratio (95% CI) Versus Ranitidine 300 mg Rabeprazole 20 mg (N = 338) Favors PPI 1.251.01.751.52.0 Favors H 2 RA 0.75 P <.05 for all PPIs vs ranitidine 300 mg Pantoprazole 40 mg (N = 249) Omeprazole 20 mg (N = 1575) Lansoprazole 30 mg (N = 948)

24. PPI Therapy Is Extremely Effective in the Majority of Patients With GERD— Comparison Studies Versus Omeprazole *P <.05 versus omeprazole. 1. Castell DO, et al. Am J Gastroenterol. 1996;91:1749-1757. 2. Mössner J, et al. Aliment Pharmacol Ther. 1995;9:321-326. 3. Dekkers C, et al. Aliment Pharmacol Ther. 1999;13:49-57. 4. Kahrilas P, et al. Aliment Pharmacol Ther. 2000;14:1249-1258. 85%-95% Rabeprazole Esomeprazole Pantoprazole Lansoprazole Omeprazole 0 20 40 60 80 100 N = 853 1 N = 286 2 N = 202 3 N = 1304 4* 8 Weeks Patients With Healed Erosive Esophagitis (%)

25. Comparison of Maintenance Therapies for Erosive Esophagitis NNT = number needed to treat. Donnellan C, et al. Cochrane Database Syst Rev. 2004;4. PPI Maintenance DoseH 2 RA PPI Healing Dose NNT = 2.9 NNT = 4.7 38 randomized, controlled trials Follow-up time: 24-52 weeks

26. Continuous Versus On-Demand PPI Therapy— Maintaining Esophagitis Healing Sjostedt S, et al. Aliment Pharmacol Ther. 2005;22:183-191. Stratified According to Baseline Los Angeles Grade Patients in Endoscopic Remission at 6 Months (%) ABCD All Patients P <.0001 93 90 80 78 65 51 44 81 58 0 10 20 30 40 50 60 70 80 90 100 Esomeprazole 20 mg QD (n = 241) Esomeprazole 20 mg on demand (n = 229) Harder to maintain healing with more severe esophagitis

27. On-Demand Therapy for Maintenance of Symptom Control*—Nonerosive GERD *After an initial acute treatment period with continuous PPI to control symptoms, asymptomatic patients were enrolled in the on-demand period. Bigard MA, Genestin E. Aliment Pharmacol Ther. 2005;22:635-643. Bytzer P, et al. Aliment Pharmacol Ther. 2004;20:181-188. Talley NJ, et al. Eur J Gastroenterol Hepatol. 2002;14:857-863. Lansoprazole 15 mg QD Rabeprazole 10 mg QD Placebo Esomeprazole 20 mg QD Esomeprazole 40 mg QD P <.05 for all PPIs vs placebo in each study

28. Key Question What constitutes PPI therapy failure? 1. Failure of the FDA-approved dose 2. Failure of 2  the FDA-approved dose 3. Failure of 2  the FDA-approved dose BID 4. Failure is not defined Use your keypad to vote now! ?

29. I typically continue evaluation after the patient has failed double-dose treatment What Is a PPI Failure?  FDA-approved dose?  2  the FDA-approved dose?  FDA-approved dose BID?  2  the FDA-approved dose BID?

30. Endoscopy GERD Symptoms? MII/pH Monitoring Excess Esophageal Acid Exposure MII/pH Monitoring Symptom Correlation GERD: Esophagitis, NERD, or Functional Heartburn? – – Functional Heartburn – Los Angeles A-D Esophagitis + NERD + NERD (hypersensitive) Weakly acidic reflux + MII = multichannel intraluminal impedance.

31. BID PPI (56) 250 GERD patients Typical (135) QD PPI (79) Abnormal pH Monitoring in Symptomatic Patients Taking PPIs  pH testing should only be performed after patients have failed double-dose PPI, if testing on medication Extra-esophageal (115) BID PPI (75) QD PPI (40) 1.2 (0%-28%) 0.3 (0%-15%) 0 (0%-4.8%) 0.3 (0%-30%) % time pH <4 24 (31%) 4 (7%) 1 (1%) 12 (30%) # abnormal Charbel S, et al. Am J Gastroenterol. 2005;100:283-289.

32. Heartburn caused by acid reflux Heartburn not caused by acid reflux  EMD  Eosinophilic esophagitis  Functional heartburn  Alkaline reflux?  Distention  Esophagitis  Histopathologic esophagitis  Healed esophagitis  Acid-sensitive esophagus  Weakly acidic reflux? Potential Etiologies of Heartburn— Not All Heartburn Is GERD EMD = esophageal motility disorder

33. Abnormal Reflux Acid mediated Non–acid mediated No Reflux  Functional  Not uniquely chemosensitive  Not uniquely mechanosensitive Nonerosive Reflux Disease

34. Reflux Treatment in 2007 Summary  Focus has shifted from esophagitis to symptom control  PPIs are the mainstay of therapy  Long-term safety is good  Minor concerns Osteoporosis Clostridium difficile colitis  Refractory or PPI unresponsive GERD requires concern for other etiology  Nonacid reflux  Functional heartburn

35. Key Question Of the following factors, which places patients at the highest risk for developing GI complications/adverse events? 1. Use of multiple NSAIDs (including aspirin) 2. Use of high-dose NSAIDs 3. Use of an anticoagulant 4. Past uncomplicated ulcer Use your keypad to vote now! NSAIDs = nonsteroidal anti-inflammatory drugs. ?

36. Burden of NSAIDs  More than 111 million NSAID/COX-2 inhibitor prescriptions written in 2004  70% of persons aged ≥65 years take NSAIDs at least weekly  60% of these patients take aspirin  34% take NSAIDs daily COX-2 = cyclooxygenase-2. IMS NPA Plus, 2004 (January 2004-December 2004). Talley NJ, et al. Dig Dis Sci. 1995;40:1345-1350. Over 100,000 hospitalizations per year due to NSAID-related complications

37. Weil J, et al. BMJ. 1995;310:827-830. Relative Risk of Upper GI Complications Aspirin 75 mg QD Aspirin 150 mg QD Aspirin 300 mg QD NSAIDs Aspirin + Other NSAIDs 0 1 2 3 4 5 6 7 8 Aspirin Alone or With Another NSAID: Risk of Upper GI Complications

38. Identify Individuals With Risk Factors for Adverse Events  Use non-NSAID analgesic whenever possible  Use the lowest effective NSAID dose *Including aspirin. Gabriel SE, et al. Ann Intern Med. 1991;115:787-796. Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772. 2.2 5.5 6.1 6.4 7 9 13.5 051015 Steroids Age >60 Years Past Uncomplicated Ulcer Anticoagulant High-Dose NSAIDs Multiple NSAIDs* Past Complicated Ulcer Odds Ratio

39. No/Low NSAID GI Risk NSAID GI Risk No CV Risk (No Aspirin) Traditional NSAID Non-NSAID therapy or COX-2 inhibitor or Gastroprotective agent with traditional NSAID CV Risk (Consider Aspirin) Non-NSAID therapy or Traditional NSAID* + gastroprotective agent if GI risk warrants gastroprotection Non-NSAID therapy or Gastroprotective agent with traditional NSAID CV = cardiovascular. *Ibuprofen should be used with caution in individuals taking aspirin. Fendrick AM, et al. Am J Manag Care. 2004;10:740-741. A Practical Guide to NSAID Therapy

40. Lazzaroni M, et al. Dig Liver Dis. 2001;33:S44-S58. Graham DY, et al. Arch Intern Med. 2002;162:169-175. Peura DA. Am J Med. 2004;117:63S-71S. Antisecretory Cotherapy TherapyAdvantagesDisadvantages Misoprostol  Reduces risk of gastric and duodenal ulcers  Reduces ulcer complications  Poor adherence  Adverse effects (diarrhea in 20% of patients)  Contraindicated in women of childbearing age H 2 RAs  Alleviate dyspeptic symptoms  Heal active ulcers only if NSAID discontinued  Ineffective in preventing gastric ulcers  Less effective than PPIs PPIs  Alleviate dyspeptic symptoms  Heal active ulcers even when NSAID is continued  Cost

41. GI Advisory Committee Consensus on NSAIDs  Recognized the CV effects of 3 COX-2 inhibitors: celecoxib, valdecoxib, and rofecoxib  Endorsed NSAID with a PPI over COX-2 inhibitors  Naproxen was the NSAID identified as most favorable  Be careful with ibuprofen + aspirin  Advised against combination therapy with aspirin and COX-2–selective agents  Endorsed using a gastroprotective agent in patients requiring aspirin plus an NSAID US FDA Arthritis Advisory Committee, Drug Safety and Risk Management Advisory Committee, February 16-18, 2005.

42. Case Study

43. Case Study: Presentation  Caucasian male aged 50 years with a history of heartburn 3 times per week  Occasional nocturnal symptoms with regurgitation and mild dysphagia  Trouble sleeping and chronic cough  Vital signs stable  Mild obesity  Otherwise normal

44. Case Study: Medical and Treatment History  Medical history includes knee replacement surgery, hypertension, hypercholesterolemia, and pulmonary embolism  Tried over-the-counter antacids and H 2 RAs for 4 weeks  Mild improvement but still had significant breakthrough symptoms  Other medications  Ibuprofen for knee pain 600 mg TID PRN  Hydrochlorothiazide  Potassium chloride  Atorvastatin  No known drug allergies

45. Decision Point How would you manage this patient? 1. 4 weeks of empiric therapy with standard-dose PPI 2. 4 weeks of empiric therapy with PPI BID 3. Switch patient to standard-dose PPI therapy and add OTC H 2 RA at bedtime 4. Check for Helicobacter pylori infection Use your keypad to vote now! ?

46. Decision Point Does this patient need any diagnostic testing and if so which test? 1. No testing needed—just treat 2. H pylori testing needed 3. Refer for endoscopy 4. Upper GI is all that is needed initially Use your keypad to vote now! ?

47. Q & A

48. PCE Takeaways

49. 1. If left untreated, GERD can progress to erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma 2. Focus of medical management of GERD is compensatory, not curative 3. 2005 ACG Practice Guidelines recommend initial trial of empiric PPI therapy if the patient’s history is typical for uncomplicated GERD

50. PCE Takeaways 1. Know when to consider further testing:  Alarm symptoms or atypical symptoms  No response to empiric therapy  The patient has sufficient duration of symptoms to be at risk for Barrett’s esophagus

51. PCE Takeaways 1. PPIs are very effective for most patients with GERD 2. PPIs are the mainstay of therapy, with good long-term safety 3. If GERD is refractory or PPI unresponsive, look for other etiology  Nonacid reflux  Functional heartburn

52. PCE Takeaways: NSAIDS 1. 15% to 30% of regular NSAID users develop ulcers, and potentially fatal complications such as GI bleeding, perforation, or obstruction occur in 1% to 2% 2. Consider antisecretory cotherapy in patients  With history of ulcer  Taking multiple NSAIDs, including aspirin  Taking high-dose NSAIDs  Taking an anticoagulant  Aged >60 years

53. Key Question In what percentage of your patients with chronic GERD will you likely initiate long-term management protocols? 1. 0%-25% 2. 26%-50% 3. 51%-75% 4. 76%-100% Use your keypad to vote now! ?