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Successful Strategies for Managing Acid-Related Disease in Primary Care

Successful Strategies for Managing Acid-Related Disease in Primary Care. Byron Cryer, MD Associate Professor of Medicine University of Texas Southwestern Medical School Dallas, Texas. ?. Key Question.

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Successful Strategies for Managing Acid-Related Disease in Primary Care

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  1. Successful Strategies forManaging Acid-Related Disease in Primary Care Byron Cryer, MD Associate Professor of Medicine University of Texas Southwestern Medical School Dallas, Texas

  2. ? Key Question 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!

  3. Faculty Disclosure • Dr Cryer: consultant: AstraZeneca Pharmaceuticals, Merck & Co., Inc., Pfizer Inc, 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? • 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! Lagergren J, et al. N Engl J Med. 1999;340:825-831.

  6. 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

  7. 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.

  8. Traditional Assumptions Concerning GERD Natural History Spectrum/Progression 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.

  9. Evolving GERD “Phenotypic Model” Progression Within the Group NERD ErosiveEsophagitis Barrett’sEsophagus Typical and Atypical Symptoms StrictureUlcerGI Bleeding Adenocarcinomaof the Esophagus Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909. Pandolfino JE, Shah N. Dig Liver Dis. 2006;38:648-651.

  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 ProgressionImportance 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 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.

  13. ? Key Question 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! Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.

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

  15. 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.

  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. 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.

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

  20. ? Key Question 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! Castell DO, et al. Am J Gastroenterol. 1996;91:1749-1757. Mössner J, et al. Aliment Pharmacol Ther. 1995;9:321-326. Dekkers C, et al. Aliment Pharmacol Ther. 1999;13:49-57. Kahrilas P, et al. Aliment Pharmacol Ther. 2000;14:1249-1258.

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

  22. 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.

  23. Omeprazole 20 mg (N = 1575) Pantoprazole 40 mg (N = 249) Meta-Analysis of PPIs Versus Ranitidine for Healing Erosive Esophagitis Healing Rate Ratio (95% CI) Versus Ranitidine 300 mg P <.05 for all PPIs vs ranitidine 300 mg Lansoprazole 30 mg (N = 948) Rabeprazole 20 mg (N = 338) 0.75 1.0 1.25 1.5 1.75 2.0 Favors PPI Favors H2RA CI = confidence interval.Caro JJ, et al. Clin Ther. 2001;23:998-1017.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. ? Key Question 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!

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

  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. 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.

  32. 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

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

  34. Reflux Treatment in 2007Summary • 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? • Use of multiple NSAIDs (including aspirin) • Use of high-dose NSAIDs • Use of an anticoagulant • Past uncomplicated ulcer Use your keypad to vote now! NSAIDs = nonsteroidal anti-inflammatory drugs. Gabriel SE, et al. Ann Intern Med. 1991;115:787-796. Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772.

  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 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  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 H2RAs 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? • 4 weeks of empiric therapy with standard-dose daily PPI • 4 weeks of empiric therapy with PPI BID • Switch patient to standard-dose PPI therapy and add OTC H2RA at bedtime • 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? • No testing needed—just treat • H pylori testing needed • Refer for endoscopy • Upper GI is all that is needed initially Use your keypad to vote now!

  47. PCE Takeaways

  48. PCE Takeaways: GERD • Acid-related disorders are common in primary care practice, and GERD prevalence is increasing • If left untreated, GERD can progress to erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma • Focus of medical management of GERD is compensatory, not curative

  49. PCE Takeaways: Empiric Therapy • 2005 ACG Practice Guidelines recommend initial trial of empiric PPI therapy if the patient’s history is typical for uncomplicated GERD • Further diagnostic testing should be considered if: • The patient has alarm symptoms or atypical symptoms • There is no response to empiric therapy • The patient has sufficient duration of symptoms to be at risk for Barrett’s esophagus

  50. PCE Takeaways: PPI Therapy • PPIs are very effective for most patients with GERD • PPIs are the mainstay of therapy, with good long-term safety • If GERD is refractory or PPI unresponsive, look for other etiology • Nonacid reflux • Functional heartburn

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