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Fall 2007 Symposia Series

St. Melville Marriott Long Island Melville, New York December 1, 2007. Fall 2007 Symposia Series. Not All Heartburn Is GERD: Successful Strategies for Managing Acid-Related Disease. John E. Pandolfino, MD Associate Professor of Medicine Feinberg School of Medicine Northwestern University

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Fall 2007 Symposia Series

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  1. St Melville Marriott Long IslandMelville, New YorkDecember 1, 2007 Fall2007Symposia Series

  2. Not All Heartburn Is GERD: Successful Strategies forManaging Acid-Related Disease John E. Pandolfino, MD Associate Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

  3. Faculty Disclosure • Dr Pandolfino: consultant/speaker/grant support: AstraZeneca, Medtronic, Inc.; speaker: Santarus, Inc.; advisory board: Crospon Ltd.

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

  5. 0 In what percentage of your patients with chronic GERD do you consider long-term management strategies? • 0%-25% • 26%-50% • 51%-75% • 76%-100% Use your keypad to vote now!

  6. 0 What overall percentage of patients with erosive esophagitis experience healing of erosions with 8 weeks of standard-dose PPI therapy? • <75% • 75%-84% • 85%-94% • 95%-100% Use your keypad to vote now!

  7. Extraesophageal GERD Esophagitis Nonerosive GERD (EGD negative) ENT Bleeding Stricture Asthma Impairs Quality of Life Barrett’s Metaplasia and Adenocarcinoma Dental EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat. GastroEsophageal Reflux Disease All individuals exposed to the physical complications from gastroesophageal reflux or who experience clinically significant impairment of health-related well being (quality of life) due to reflux-related symptoms Genval Working Group 1997

  8. GERD Severity ≈ Pathophysiologic Determinants of Esophagitis Severity and Chronicity Aggressive Factors Causticity of gastric juice N of reflux events • Chronic condition usually not attributed to excess acid secretion • Number of acid reflux events and caustic nature of refluxate are primary determinants of GERD severity • Tissue resistance and acid clearance also contribute • Treatment approaches are compensatory, rather than curative • Therapeutic focus is on refluxate causticity • Few existing medical therapies affect the number of reflux events • No noninvasive therapies to correct GERD-associated anatomical and motor abnormalities  Defensive Factors Acid clearance Tissue resistance  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.

  9. Focus of Medical Management of GERD—Compensatory, Not Curative It’s all about acid! • PPIs • H2RAs • Antacids H2RAs =histamine2-receptor antagonists.

  10. Meta-Analysis of PPIs, H2RAs, and Placebo for Healing Erosive Esophagitis (n) = Number of studies 100 (2) (3) PPIs (26) 80 (27) (4) (22) H2RAs 60 (25) Total Healed (%) (25) (23) 40 (9) (2) Placebo (5) (8) (5) 20 0 2 4 6 8 12 Therapy (weeks) Chiba N, et al. Gastroenterology. 1997;112:1798-1810.

  11. PPI Therapy Is Extremely Effective in the Majority of Patients With GERD—Comparison Studies Versus Omeprazole 100 85%-95% 80 Omeprazole Lansoprazole 60 Pantoprazole Patients With Healed Erosive Esophagitis (%) 40 Rabeprazole Esomeprazole 20 0 N = 8531 N = 2862 N = 2023 N = 13044* 8 Weeks *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.

  12. Comparison of Maintenance Therapies for Erosive Esophagitis PPI healing dose PPI maintenance dose H2RA 38 randomized, controlled trials Follow-up time: 24-52 weeks NNT = 4.7 NNT = 2.9 NNT = number needed to treat.Donnellan C, et al. Cochrane Database Syst Rev. 2004;4.

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

  14. Esomeprazole 20 mg QD Esomeprazole 40 mg QD Lansoprazole 15 mg QD Placebo On-Demand Therapy for Maintenance of Symptom Control*—Nonerosive GERD Rabeprazole 10 mg QD P <.05 for all PPIs vs placebo in each study *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.

  15. Summary of GERD Treatment • PPIs are the mainstay of therapy • Chronic PPI therapy indicated for: • Esophagitis • Symptoms greater than 3/week • PPI on-demand therapy may be reasonable for: • Mild NERD • Mild esophagitis Kahrilas PJ, et al. In: Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. Philadelphia, Pa: WB Saunders Co; 2002:599-622.

  16. PPIs Have a Good Long-term Safety Profile Minor Concerns • Osteoporosis • Increased risk of hip fractures • Adjusted OR 2.65 (1.8-3.9) • Enteric infection • Increased risk of Clostridium difficile infection in PPI users • Risk increased from 0.02% to 0.06% • Pneumonia • Flawed study, with no control for important confounders • Vitamin B12 deficiency • Data conflicting Dial S, et al. JAMA. 2005;294:2989-2995. Laheij RJ, et al. JAMA. 2004;292:1955-1960. Yang YX, et al. JAMA. 2006;296:2947-2953.

  17. 0 Approximately what percentage of patients presenting to general practices with GERD symptoms have normal mucosa or erythema only on endoscopy? • 75% • 55% • 35% • 15% Use your keypad to vote now!

  18. 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.

  19. Algorithm for Diagnostic Referral in Patients Presenting With GERD Symptoms History and Physical Examination • Early Referral Symptoms • Dysphagia/odynophagia • Early satiety • Persistent vomiting • GI bleeding • Weight loss • Fever Typical Symptoms Only • Heartburn • Regurgitation • 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.

  20. Endoscopy • Indications: • Dysphagia/odynophagia • Persistent vomiting • Anorexia • Unintentional weight loss • Anemia • Fever • Gastrointestinal bleeding (occult or overt) These symptoms indicate a high risk for complications or an alternative diagnosis DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.

  21. 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.

  22. Endoscopy

  23. Eosinophilic Esophagitis Can Mimic GERD • “Allergic esophagus” – infiltrative eosinophilia • Increasing incidence vs underrecognized • Signs/symptoms: • Dysphagia, food impaction, abdominal/chest pain, vomiting, regurgitation • Clinical characteristics • Male predominance (70%-80% of cases) • Family or personal history of allergy/atopy • Asthma, rhinitis, eczema, food allergy Eos GERD Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530. Liacouras CA, et al. Clin Gastroenterol Hepatol. 2005;3:1198-1206.

  24. Differentiating GERD From Eosinophilic Esophagitis Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530. Liacouras CA, et al. Clin Gastroenterol Hepatol. 2005;3:1198-1206.

  25. Management of Eosinophilic Esophagitis • Medical therapy can lead to resolution ofsymptoms and stricture • Treatment • PPI • Steroids (fluticasone, prednisone) • Diet (wheat, soy, milk, peanuts, and/or seafood) • Allergy evaluation? Dilation therapy Attwood SE, et al. Dig Dis Sci. 1993;38:109-116. Liacouras CA, et al. Clin Gastroenterol Hepatol. 2005;3:1198-1206.

  26. Pill Esophagitis Can Mimic GERD N = 92 Other antibiotics 40% 8% NSAIDs (including aspirin) Tetracyclines 22% 7% Quinidine 4% 10% 9% Ascorbic acid Potassium chloride Alendronate NSAIDs = nonsteroidal anti-inflammatory drugs. Abid S, et al. Endoscopy. 2005;37:740-744.

  27. 0 What constitutes PPI therapy failure? • Failure of the FDA-approved dose • Failure of 2  the FDA-approved dose • Failure of 2  the FDA-approved dose BID • Failure is not defined Use your keypad to vote now!

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

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

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

  31. Catheter-Based Impedance andpH Monitoring • Best test for reflux detection • Uncomfortable • Cumbersome • Inconvenient Fass R, et al. Dig Dis Sci. 1999;44:2263-2269.

  32. Acid Reflux: Impedance Impedance pH Time 2 sec Vela MF, et al. Gastroenterology. 2001;120:1599-1606.

  33. Nonacid Reflux: Impedance Impedance pH Time 2 sec Vela MF, et al. Gastroenterology. 2001;120:1599-1606.

  34. Suction applied Probe released from attachment device Improved Patient Tolerance: Getting Rid of the Catheter Attachment device positioned Attachment pin fired Attachment device removed Recording begins

  35. 48-Hour Telemetry Probe: pH Tracing in GERD Patient

  36. Refractory GERD Symptoms (Endoscopy Negative) No Reflux Abnormal Reflux Non-acid mediated Acid mediated • Functional • Not uniquely chemosensitive • Not uniquely mechanosensitive

  37. Summary: Management of PPI-Refractory GERD Symptoms • Refractory acid reflux on double-dose PPI is rare • 7% for typical symptoms • 1% for atypical symptoms • Failure of double-dose PPI should lead to a search for an alternative diagnosis • Non-acid reflux • Functional heartburn • Eosinophilic esophagitis • Esophageal motor disorder

  38. 0 Which of the following increases a person’s risk of developing esophageal adenocarcinoma? • Long-standing GERD symptoms • Frequent GERD symptoms • Both of the above • No study has connected GERD symptom characteristics and adenocarcinoma risk Use your keypad to vote now!

  39. 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.

  40. Summary of Disease ProgressionBarrett’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. Lagergren J, et al. N Engl J Med. 1999;340:825-831.

  41. ACG Guidelines for Barrett’s Esophagus Sampliner RE, et al. Am J Gastroenterol. 2002;97:1888-1895.

  42. 0 Of the following factors, which places patients at the highest risk for developing GI complications/adverse events? • Use of multiple NSAIDs (including aspirin) • Use of high-dose NSAIDs • Use of an anticoagulant • Past uncomplicated ulcer Use your keypad to vote now!

  43. 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 Over 100,000 hospitalizations per year due to NSAID-related complications COX-2 = cyclooxygenase-2. IMS NPA Plus, 2004 (January 2004-December 2004). Talley NJ, et al. Dig Dis Sci. 1995;40:1345-1350.

  44. Aspirin Alone or With Another NSAID: Risk of Upper GI Complications 8 7 6 5 Relative Risk of Upper GI Complications 4 3 2 1 0 Aspirin75 mgQD Aspirin150 mgQD Aspirin300 mgQD NSAIDs Aspirin + OtherNSAIDs Weil J, et al. BMJ. 1995;310:827-830.

  45. 13.5 Past Complicated Ulcer 9 Multiple NSAIDs* 7 High-Dose NSAIDs 6.4 Anticoagulant 6.1 Past Uncomplicated Ulcer 5.5 Age >60 Years 2.2 Steroids 0 5 10 15 Identify Individuals With Risk Factors for Adverse Events • Use non-NSAID analgesic whenever possible • Use the lowest effective NSAID dose Odds Ratio *Including aspirin. Gabriel SE, et al. Ann Intern Med. 1991;115:787-796. Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772.

  46. A Practical Guide to NSAID Therapy CV = cardiovascular. *Ibuprofen should be used with caution in individuals taking aspirin. Fendrick AM, et al. Am J Manag Care. 2004;10:740-741.

  47. Antisecretory Cotherapy 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.

  48. 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.

  49. Case Study

  50. 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

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