1. Chest pain of unknown origin (CPUO): role of the esophagus Richard I. Rothstein, MD Chief, Section of Gastroenterology and Hepatology Dartmouth Hitchcock Medical Center Professor of Medicine Dartmouth Medical School

2. Chest Pain of Unknown Origin

3. Prognosis for angina-like pain with normal coronary anatomy Chambers, Prog Cardiovasc Dis 1990 Kemp, Am J Med 1973

4. Functional Status – normal coronary anatomy Ockene N Engl J Med 1980

5. Reflux common in pts with coronary disease Singh, Ann Intern Med,1992; 117:824-30 n = 30, 164 chest pain episodes

6. Abnormal esophageal motility (n = 910) (n = 255) Katz, Ann Intern Med, 1987; 106:593-7

7. Edrophonium Testing 80 mcg/Kg IV

8. Diagnostic Yield of Esophageal Testing Katz, Ann Intern Med, 1987; 106:593-7

9. Intraesophageal Balloon Inflation: Esophageal Hypersensitivity n = 30 NCCP, 30 controls Richter, Gastroenterol, 1986; 91:845-52

10. Provocative Testing Barrish, Dig Dis Sci, 1986; 31:1292-8

11. WithEsophagealSymptomsIsolatedChestPain Subgroups of Patients With Chest Pain Anxiety/SomatizationNeurosis

12. Rare for esophageal pathology Rare for esophageal pathology Question the “non-cardiac” Question the “non-cardiac” Reassurance, tincture of time Reassurance, tincture of time Subgroups of Patients With Chest Pain IsolatedChestPain

13. Heartburn Heartburn Regurgitation Regurgitation Dysphagia Dysphagia Water brash Water brash Nausea Nausea Vomiting Vomiting Evaluate or treat for recognized esophageal disorders WithEsophagealSymptoms Subgroups of Patients With Chest Pain

14. Endoscopy Detection of Esophageal Disorders Potentially Responsible for Symptoms pH EGD-negative GERD EGD-negative GERD Barium swallow ± manometry Esophageal stricture/web Esophageal stricture/web Achalasia Achalasia Esophageal spasm Esophageal spasm Reflux esophagitis Reflux esophagitis Infectious esophagitis Infectious esophagitis Pill esophagitis Pill esophagitis Esophageal cancer Esophageal cancer Esophageal stricture/web Esophageal stricture/web

15. pH testing - Conventional Catheter Based:  Patient Intolerance  Uncomfortable  Pharyngeal and Throat Discomfort  Runny Nose  Artifact Prone  Alters Regular Diet and Activity

16. Catheter-Free pH Monitoring System pH Capsule attached to the esophageal wall transmits data to pager-sized Receiver Eliminates uncomfortable 24-hr trans-nasal catheter Allows normal activities, showering and does not interfere with sleeping Bravo pH System™

17. pH Capsule Catheter Handle Bravo pH Capsule with Delivery System

18. Step 1 Position Bravo Capsule Step 2 Apply Suction Step 3 Advance Pin Step 5 Begin pH Recording Step 4 Release Capsule Capsule Attachment

19. pH Capsule transmits data to pager-sized Receiver pH Capsule Receiver Bravo pH Receiver

20. Use Digital Radio- Telemetry Capsule measures pH every 6 sec and transmits data to receiver every 12 sec Keep the receiver within 1m to prevent data loss (range up to 3m) Digital Radio-Telemetry

23. Esophageal Testing in 123 Patients with Chest Pain and Normal Coronary Arteriograms Test% Abnormal Ambulatory pH monitoring82 Esophageal motility29 Bernstein Test10 Edrophonium6 Endoscopy5 Balloon distention4 Treadmill with pH monitor4 Chenan P, et al Dis Esophagus 1995; 8:129

24. Atypical presentations of GERD Pulmonary  Asthma  Bronchitis  Aspiration pneumonia  Apnea  Atelectasis  Pulmonary fibrosis ENT  Hoarseness  Cough  Globus  Halitosis  Vocal cord granuloma  Laryngeal stenosis  Laryngeal cancer  Loss of dental enamel  Sinusitis, otitis Chest Pain

25. Esophageal Chest Pain Work-Up  Traditionally  Endoscopy  pH probe  Manometry  Provocative testing  Emerging role for up-front empiricism

26. Fass et al. Gastroenterology. 1998;115:42-49. GERD-Positive n=23 n=23 78% response 78% responseGERD-Negative n=14 n=14 14% response 14% response PPI Trial in GERD Patients With Non-Cardiac Chest Pain  37 patients with daily chest pain and negative cardiologic evaluation  Categorized as GERD+ or GERD- by EGD and pH study  Randomized to omeprazole (40 mg q AM and 20 mg q PM for 7 days) or placebo then crossed over after washout  50% reduction in symptoms constituted positive response

27. Characteristics of the Patients Patients with NCCP GERD-positiveGERD-negative Fass R, et al Gastroenterol 1998; 115:42-9 Subjects2314 Age (yr)58.2±2.361.6±2.8 Range (yr) 35-76 47-83 Range (yr) 35-76 47-83 Sex (M / F) 22 / 1 14 / 0 Upper endoscopy results Normal (grade 0-1)714 Normal (grade 0-1)714 Erosive esophagitis (grade 2-5)16 Erosive esophagitis (grade 2-5)16 Ambulatory 24-h esophageal pH monitoring (%)* monitoring (%)* Mean9.6±1.81.2±0.3 Mean9.6±1.81.2±0.3 Range 0.5-29.1 0.0-2.9 Range 0.5-29.1 0.0-2.9 *% total time pH<4

28. Enrollment Upper endoscopy & Ambulatory 24-hour esophageal pH monitoring GERD + GERD - Baseline symptom assessment Randomization Placebo Omeprazole (40 mg AM + 20 mg PM) Washout period Baseline symptom assessment Omeprazole Placebo Omeprazole Placebo (40 mg AM + 20 mg PM) Week 1 Week 2 Week 3 Week 4 Week 5 Fass R, et al Gastroenterol 1998; 115:42-9

29. Omeprazole Test in NCCP  18/23 GERD-positive (78%)  2/14 GERD-negative (14%)  Sensitivity 78.3%  Sensitivity 85.7%  59% reduction in number of diagnostic procedures ($573 savings per patient evaluation) ($573 savings per patient evaluation) Fass R, et al Gastroenterol 1998; 115:42-9 Positive OT

30. Results of Economic Analysis Conventional work-upOTDifference% Change Cost ($)2025145257328 Reduction No. of endoscopies/ 1000 patients100019081081 Reduction 1000 patients100019081081 Reduction No. of ambulatory 24-hr pH tests/ 24-hr pH tests/ 1000 patients65014051079 Reduction 1000 patients65014051079 Reduction No. of esophageal motility tests / motility tests / 1000 patients310470-16052 Increase 1000 patients310470-16052 Increase Total no. of diagnostic procedures / procedures / 1000 patients1960800116059 Reduction 1000 patients1960800116059 Reduction Fass R, et al Gastroenterol 1998; 115:42-9

31. Omeprazole Test in NCCP  Generalizability?  Male, veteran population  High % esophagitis, GERD symptoms  Pain pattern of frequent chest pain (≥ 3x/wk)  Small numbers, short course treatment  Medication dosing, strength  Role of endoscopy  Reassurance factor  Once-in-a-lifetime Barrett’s check Issues

33. LA Grade C LA Grade D One or more mucosal breaks no longer than 5mm, not bridging the tops of mucosal folds One or more mucosal breaks bridging the tops of mucosal folds involving <75% of the circumference One or more mucosal breaks bridging the tops of mucosal folds involving >75% of the circumference One or more mucosal breaks longer than 5mm, not bridging the tops of mucosal folds LA Grade B LA Grade A Los Angeles (LA) Grade Classification of Erosive Esophagitis Lundell et al. Gut. 1999;45:172-180.

34. The spectrum of heartburn frequency and severity is similar in GERD patients with and without esophagitis Severe Moderate Mild Patients without esophagitis Severity of heartburn Smout 1997 Patients with esophagitis

35. GERD Therapeutic Options Prokinetics OTC or prescription H2RAs “First - aid” : Life-style modifications and antacids Endoscopic techniques (plication, RF, implant) Surgery (Lap Nissen fundoplication) OTC or prescription PPIs Treatments

36. Life-style Modifications Reduce weight Elevate head of bed Stop smoking Eat small meals, no late meals, reduce fat Consider alternatives to reflux-promoting drugs e.g., theophilline, anticholinergics Avoid reflux-promoting agents e.g, alcohol, coffee; some foods  Not evidence-based Modifications

38. POSITION AND REFLUX Right side down Left side down pH 0 0 4 4 8 8 (Katz,LC. Et al, J Clin Gastro 1994;18(4):280-3

39. GERD HEALING AND ACID CONTROL (Bell et al. Digestion. 1992;51(suppl 1):59-67.) Patients Healed (%) Duration Intragastric pH >4.0 (Hours) 100 80 60 40 20 0 246810121416182022

40. Medical Rx Outcomes (with H2RAs)  Relief of symptoms 50%  Healing esophagitis<50%  Prevent complications ---  Remission25%

41. Medical Rx Outcomes (PPIs)  Relief of symptoms 85-95%  Healing esophagitis85-95%  Prevent complications80%  Remission90%

42. GERD: Endoscopic Therapies  Endoscopic suturing – i.e., Endocinch (this leads to partial thickness plication)  Full thickness plication – i.e., NDO  Radiofrequency ablation – i.e., Stretta  Injection therapy with augmentation of LES – i.e., Enteryx  Bulking procedures with augmentation of LES – i.e., Gatekeeper

43. BARD EndoCinch BARD EndoCinch Suction of tissue just beneath z-line Needle with pre-loaded suture advanced Cinching/cutting catheter advanced to tissue Final appearance of plication in cardia

44. NDO Plicator™ Plicator and gastroscope retroflexed Arms opened, tissue retractor advanced Gastric wall retracted, arms closed. Single, pre-tied implant deployed. Full-thickness plication completed 1 23 45

45. Antegrade technique Balloon inflation Needle deployment 1 cm above z-line

46. Injection at the Z-Line

47. Gatekeeper™ System Stabilize site Expansion Deliver prosthesis Create pocket Access pocket

48. MAINTENANCE THERAPY OF GERD Omeprazole vs surgery (Lundel et al: J Am Col Surg, 192:172, 2001)

49.  150 consecutive laparoscopic antireflux surgery patients  35 treated primarily for atypical symptoms So et al. Surgery. 1998;124:28-32. Pulmonary Sx Asthma Asthma Chronic cough Chronic cough n=16 n=16 n=12 n=12 Pharyngo/laryngeal Sx Hoarseness Hoarseness Globus Globus Halitosis/Dental Halitosis/Dental Sore throat Sore throat n=9 n=9  Independent observer assessment  GERD by EGD, ambulatory pH, or free reflux on x-ray (n=2)  86% used OTC GERD meds; not dominant symptom in any  ENT/cardiological evaluation excluded other causes Outcomes of Atypical GERD Symptoms Treated by LNF Atypical chest pain or epigastric pain

50. Symptom Score So et al. Surgery. 1998;124:28-32. Typical Symptoms (n=115) Typical Symptoms (n=115) Improvement 6.2 points Atypical Symptoms (n=35) Atypical Symptoms (n=35) Improvement 4.4 points Atypical Sx Improvement Overall 58% of patients Overall 58% of patients –Pulmonary 48% –Atypical chest pain 58% –Pharyngo/ laryngeal 76% Outcomes of Atypical GERD Symptoms Treated by LNF PreoperativePostoperative

51. Esophageal Chest Pain  GERD related  Motility related  Esophageal hyperalgesia

52. Esophageal Hyperalgesia  “Irritable esophagus”  Abnormal nociception  Lower threshold for pain

53. Esophageal Hyperalgesia  Noxious stimulus in esophagus  Decrease in nociceptor threshold  Disorder of CNS nociceptive pathway

54. Chest Pain - Imipramine  50 mg nightly for 3 wks  52% reduction in chest pain episodes  Suggested visceral analgesic effect Cannon R, et al. N Engl J Med 1994; 330:1411-7  15 healthy male volunteers  Balloon inflation volume at pain threshold higher on imipramine Peghini PL, et al. Gut 1998; 42:807-13

55. NCCP Non-GERD Esophageal Therapies  Calcium channel blockers  Anticholinergics  Nitrates  Botox  Antidepressants (Imipramine, Trazodone)  Octreotide  Bougienage  5 HT 3 antagonists

56. Initial Perception Threshold (S1) Before and 40 Minutes after Octreotide Injection Base 40 min 0 10 20 30 >30 CC p < 0.02 Johnson BT, et al Am J Gastroenterol 1999; 94:65-70

57. Maximally Tolerated Pain Threshold (S2) Before and 40 Minutes after Octreotide Injection Base 40 min 0 10 20 30 >30 CC Johnson BT, et al Am J Gastroenterol 1999; 94:65-70

58. Overlap Syndrome of Altered Pain Sensitivity

59. Approach to the NCCP Patient  Take a history  Exclude coronary / cardiac disease  Check for musculoskeletal disease  Look for GERD  Check for dysmotility  Consider esophageal hyperalgesia  Collaborative management